U.S. patent application number 11/768338 was filed with the patent office on 2007-11-08 for 3-substituted quinoline-4-carboxamide derivatives as nk-3 and nk-2 receptor antagonists.
This patent application is currently assigned to GlaxoSmithKline S.P.A.. Invention is credited to Carlo FARINA, Stefania Gagliardi, Giuseppe Arnaldo, Maria Giardina, Marisa Martinelli.
Application Number | 20070259882 11/768338 |
Document ID | / |
Family ID | 26245967 |
Filed Date | 2007-11-08 |
United States Patent
Application |
20070259882 |
Kind Code |
A1 |
FARINA; Carlo ; et
al. |
November 8, 2007 |
3-SUBSTITUTED QUINOLINE-4-CARBOXAMIDE DERIVATIVES AS NK-3 AND NK-2
RECEPTOR ANTAGONISTS
Abstract
A compound of formula (I) below or a pharmaceutically acceptable
salt or solvate thereof: ##STR1##
Inventors: |
FARINA; Carlo; (Baranzate di
Bollate, IT) ; Gagliardi; Stefania; (Baranzate di
Bollate, IT) ; Giardina; Giuseppe Arnaldo, Maria;
(Baranzate di Bollate, IT) ; Martinelli; Marisa;
(Baranzate di Bollate, IT) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
GlaxoSmithKline S.P.A.
|
Family ID: |
26245967 |
Appl. No.: |
11/768338 |
Filed: |
June 26, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11426956 |
Jun 28, 2006 |
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11768338 |
Jun 26, 2007 |
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10474557 |
Apr 26, 2004 |
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PCT/EP02/04070 |
Apr 11, 2002 |
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11426956 |
Jun 28, 2006 |
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Current U.S.
Class: |
514/253.06 ;
544/363 |
Current CPC
Class: |
C07D 401/04 20130101;
A61P 7/12 20180101; A61P 11/00 20180101; A61P 25/22 20180101; A61P
7/10 20180101; C07D 401/14 20130101; A61P 13/02 20180101; C07D
409/04 20130101; A61P 7/00 20180101; A61P 9/08 20180101; C07D
487/04 20130101; A61P 25/16 20180101; A61P 25/04 20180101; A61P
9/00 20180101; A61P 29/00 20180101; A61P 27/16 20180101; C07D
215/50 20130101; A61P 25/06 20180101; A61P 21/00 20180101; A61P
25/30 20180101; A61P 7/04 20180101; A61P 19/02 20180101; A61P 17/04
20180101; A61P 25/08 20180101; A61P 25/00 20180101; C07D 215/52
20130101; A61P 25/14 20180101; A61P 37/08 20180101; A61P 13/12
20180101; A61P 43/00 20180101; A61P 9/12 20180101; A61P 25/02
20180101; C07D 417/06 20130101; A61P 37/06 20180101; A61P 25/32
20180101; A61P 27/02 20180101; A61P 25/24 20180101; A61P 25/18
20180101; A61P 17/00 20180101; C07D 401/06 20130101; A61P 1/14
20180101; C07D 215/16 20130101; A61P 31/04 20180101; C07D 409/14
20130101; A61P 25/28 20180101; A61P 1/04 20180101; A61P 1/00
20180101; A61P 11/06 20180101; A61P 17/06 20180101; A61P 37/04
20180101 |
Class at
Publication: |
514/253.06 ;
544/363 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61P 25/00 20060101 A61P025/00; C07D 401/00 20060101
C07D401/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2001 |
GB |
0109123.0 |
Mar 11, 2002 |
GB |
0205649.7 |
Claims
1. The compound
6,7-Difluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxyl-
ic acid ((S)-1-cyclohexyl-ethyl)-amide, or a pharmaceutically
acceptable salt thereof.
2. A pharmaceutical composition comprising the compound according
to claim 1 and a pharmaceutically acceptable carrier.
3. A method of treating anxiety, depression, psychosis, or
schizophrenia comprising administering to a subject in need of
treatment, a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
4. The compound
6-Fluoro-3-(2-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide, or a pharmaceutically
acceptable salt thereof.
5. A pharmaceutical composition comprising the compound according
to claim 4 and a pharmaceutically acceptable carrier.
6. A method of treating anxiety, depression, psychosis, or
schizophrenia comprising administering to a subject in need of
treatment, a compound according to claim 4, or a pharmaceutically
acceptable salt thereof.
Description
[0001] This application is a continuation of application Ser. No.
11/426,956, filed Jun. 28, 2006, which is a continuation of
application Ser. No. 10/474,557, filed Apr. 26, 2004, which is a
371 of International Application No. PCT/EP02/04070, filed Apr. 11,
2002.
[0002] The present invention relates to novel compounds, in
particular to novel quinoline derivatives, to processes for the
preparation of such compounds, to pharmaceutical compositions
containing such compounds and to the use of such compounds in
medicine.
[0003] The mammalian peptide Neurokinin B (NKB) belongs to the
Tachykinin (TK) peptide family which also include Substance P(SP)
and Neurokinin A (NKA). Pharmacological and molecular biological
evidence has shown the existence of three subtypes of TK receptor
(NK.sub.1, NK.sub.2 and NK.sub.3) and NKB binds preferentially to
the NK.sub.3 receptor although it also recognises the other two
receptors with lower affinity (Maggi et al, 1993, J. Auton.
Pharmacol., 13, 23-93).
[0004] Selective peptidic NK.sub.3 receptor antagonists are known
(Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with
peptidic NK.sub.3 receptor agonists suggest that NKB, by activating
the NK.sub.3 receptor, has a key role in the modulation of neural
input in airways, skin, spinal cord and nigro-striatal pathways
(Myers and Undem, 1993, J. Physiol., 470, 665-679; Counture et al.,
1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J.
Neurosci., 14 (2), 712-720; Arenas et al. 1991, J. Neurosci., 11,
2332-8). However, the peptide-like nature of the known antagonists
makes them likely to be too labile from a metabolic point of view
to serve as practical therapeutic agents.
[0005] International Patent Application, Publication Number WO
00/58307 describes a series of aryl fused 2,4-disubstituted
pyridines, such as naphthyridine derivatives, which are stated to
exhibit biological activity as NK.sub.3 receptor antagonists.
[0006] The compounds of the present invention are quinoline
derivatives. Other quinoline derivatives have been described
previously as selective NK.sub.3 antagonists. For example,
International Patent Application, Publication Numbers, WO 95/32948
and WO 96/02509 describe a series of selective and potent NK.sub.3
receptor antagonists.
[0007] International Patent Application, Publication Number WO
00/64877 describes a series of 2-aminoquinolinecarboxamides as
neurokinin receptor ligands.
[0008] International Patent Application, Publication Number, WO
00/58303 describes a series of 4-substituted quinoline derivatives
which are stated to be NK.sub.3 and/or GABA(A) receptor ligands.
Such compounds are characterised by the presence of a
nitrogen-containing heterocyclic moiety at the C(4) position of the
quinoline ring.
[0009] International Patent Application, Publication Numbers, WO
97/21680, WO 98/52942, WO 00/31037 and WO 00/31038 describe
compounds which have biological activity as combined NK.sub.3 and
NK.sub.2 receptor antagonists.
[0010] Copending International Patent Application Numbers,
PCT/EP01/13833, PCT/EP01/14140 and PCT/EP01/13832 also describe
compounds that have biological activity as combined NK.sub.3 and
NK.sub.2 receptor antagonists.
[0011] We have now discovered a further novel class of non-peptide
NK.sub.3 antagonists which are far more stable from a metabolic
point of view than the known peptidic NK.sub.3 receptor antagonists
and are of potential therapeutic utility. These compounds also have
NK.sub.2 antagonist activity and are therefore considered to be of
potential use in the prevention and treatment of a wide variety of
clinical conditions, which are characterised by overstimulation of
the Tachykinin receptors, in particular NK.sub.3 and NK.sub.2.
[0012] These conditions include respiratory diseases, such as
chronic obstructive pulmonary disease (COPD), asthma, airway
hyper-reactivity, cough; inflammatory diseases such as inflammatory
bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid
arthritis and inflammatory pain; neurogenic inflammation or
peripheral neuropathy, allergies such as eczema and rhinitis;
ophthalmic diseases such as ocular inflammation, conjunctivitis,
vernal conjuctivitis and the like; cutaneous diseases, skin
disorders and itch, such as cutaneous wheal and flare, contact
dermatitis, atopic dermatitis, urticaria and other eczematoid
dermatitis; adverse immunological reactions such as rejection of
transplanted tissues and disorders related to immune enhancement or
suppression such as systhemic lupus erythematosis; gastrointestinal
(GI) disorders and diseases of the GI tract such as disorders
associated with the neuronal control of viscera such as ulcerative
colitis, Crohn's disease, irritable bowel syndrome (IBS),
gastro-exophageous reflex disease (GERD); urinary incontinence and
disorders of the bladder function; renal disorders; increased blood
pressure, proteinuria, coagulopathy and peripheral and cerebral
oedema following pro-eclampsia in pregnancies (hereinafter referred
to as the `Primary Conditions`).
[0013] Certain of these compounds also show CNS activity and hence
are considered to be of particular use in the treatment of
disorders of the central nervous system such as anxiety,
depression, psychosis and schizophrenia; neurodegenerative
disorders such as AIDS related dementia, senile dementia of the
Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's
disease, Parkinson's disease, movement disorders and convulsive
disorders (for example epilepsy); demyelinating diseases such as
multiple sclerosis and amyotrophic lateral sclerosis and other
neuropathological disorders such as diabetic neuropathy, AIDS
related neuropathy, chemotherapy-induced neuropathy and neuralgia;
addiction disorders such as alcoholism; stress related somatic
disorders; reflex sympathetic dystrophy such as shoulder/hand
syndrome; dysthymic disorders; eating disorders (such as food
intake disease); fibrosing and collagen diseases such as
scleroderma and eosinophilic fascioliasis; disorders of the blood
flow caused by vasodilatation and vasospastic diseases such as
angina, migraine and Reynaud's disease and pain or nociception, for
example, that is attributable to or associated with any of the
foregoing conditions especially the transmission of pain in
migraine, (hereinafter referred to as the `Secondary
Conditions`).
[0014] The compounds of formula (I) are also considered to be
useful as diagnostic tools for assessing the degree to which
neurokinin-3 and neurokinin-2 receptor activity (normal,
overactivity or underactivity) is implicated in a patient's
symptoms.
[0015] The compounds of the present invention have also been found
to exhibit surprisingly advantageous pharmacochemical
properties.
[0016] According to the present invention, there is provided a
compound of formula (I) below or a pharmaceutically acceptable salt
or solvate thereof: ##STR2## wherein: R.sub.1 is H or alkyl;
R.sub.2 is aryl or cycloalkyl or heteroaryl; R.sub.3 is H or alkyl,
wherein the alkyl group may be optionally substituted by one or
more fluorine atoms; R.sub.4 is H, hydroxyalkyl, dihydroxyalkyl or
hydroxyalkoxyalkyl; R.sub.5 is branched or linear alkyl,
cycloalkyl, cycloalkylalkyl, aryl, or a single or fused ring
aromatic heterocyclic group; R.sub.6 represents H or up to three
substituents independently selected from the list consisting of:
alkyl, alkenyl, aryl, alkoxy, hydroxy, halo, nitro, cyano, carboxy,
carboxamido, sulphonamido, trifluoromethyl, or amino or mono- or
di-alkylamino; R.sub.7 is H or halo; R.sub.8 is H or .dbd.O; and
any of R.sub.2 and R.sub.5 may optionally be substituted one or
more times by halo, hydroxy, amino, cyano, nitro, carboxy, oxo,
alkyl, alkenyl, aryl, alkoxy, carboxamido, sulphonamido,
trifluoromethyl, or mono- or di-alkylamino; with the proviso that
said compound of formula (I) is not a compound selected from:
[0017] 2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
((S)-1-phenyl-ethyl)-amide; [0018]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
[(S)-1-(4-methoxy-phenyl)-ethyl]-amide; [0019]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
[(S)-1-(3-methoxy-phenyl)-ethyl]-amide; [0020]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
[(S)-1-(3-hydroxy-phenyl)-ethyl]-amide; [0021]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
((R)-1-cyclohexyl-ethyl)-amide; [0022]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
[(S)-1-(4-hydroxy-phenyl)-ethyl]-amide; [0023]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
(1-methyl-1-phenyl-ethyl)-amide; [0024]
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
(1-cyclohexyl-1-methyl-ethyl)-amide; [0025]
6-Fluoro-2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0026]
6-Chloro-2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0027]
3-(3-Oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide; [0028]
3-(2-Oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide; [0029]
6-Fluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0030]
(4-Benzyl-3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0031]
7-Chloro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0032]
7-Fluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0033]
8-Fluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0034]
3-(3-Oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-1-phenyl-propyl)-amide; [0035]
3-(3-Oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0036]
3-(3-Oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-2-methyl-1-phenyl-propyl)-amide; [0037]
2-(4-Fluoro-phenyl)-3-(3-oxo-piperazin-1-ylmethyl)-quinoline-4-carboxylic
acid ((S)-cyclohexyl-ethyl)-amide; [0038]
3-(3-Oxo-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-quinoline-4-c-
arboxylic acid ((S)-cyclohexyl-ethyl)-amide; [0039]
2-(2-Fluoro-phenyl)-3-(3-oxo-piperazin-1-ylmethyl)-quinoline-4-carboxylic
acid ((S)-cyclohexyl-ethyl)-amide; [0040]
3-(3-Oxo-piperazin-1-ylmethyl)-2-phenyl-6-trifluoromethyl-quinoline-4-car-
boxylic acid ((S)-1-cyclohexyl-ethyl)-amide; and [0041]
3-(3-Oxo-piperazin-1-ylmethyl)-2-phenyl-7-trifluoromethyl-quinoline-4-car-
boxylic acid ((S)-1-cyclohexyl-ethyl)-amide. Preferably, R.sub.1 is
H. Suitably, R.sub.2 is aryl or cycloalkyl. Preferably, R.sub.2 is
phenyl or cyclohexyl. Suitably, R.sub.3 is alkyl. Preferably,
R.sub.3 is methyl. Suitably, R.sub.4 is H, --(CH.sub.2).sub.2OH,
--(CH.sub.2).sub.3OH, --(CH.sub.2).sub.2(OH)CH.sub.2(OH), or
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2OH; Suitably, R.sub.5 is
aryl or an aromatic heterocyclic group. Preferably, R.sub.5 is
phenyl, 2-thienyl or 3-thienyl. Suitably, R.sub.6 is H or fluoro.
Suitably, R.sub.7 is H or fluoro.
[0042] In a preferred aspect of the present invention, there is
provided a subset of compounds of formula (I), of formula (IA), or
a pharmaceutically acceptable salt or solvate thereof: ##STR3##
wherein, R.sub.1 is H; R.sub.2 is aryl or cycloalkyl; R.sub.3 is
alkyl; R.sub.4 is H, --(CH.sub.2).sub.2OH, --(CH.sub.2).sub.3OH,
--(CH.sub.2).sub.2(OH)CH.sub.2(OH), or
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2OH; R.sub.5 is aryl or an
aromatic heterocyclic group; R.sub.6 is H or halo; and R.sub.7 is H
or halo. Preferably, R.sub.2 is phenyl or cyclohexyl. Preferably,
R.sub.3 is methyl. Preferably, R.sub.5 is phenyl, 2-thienyl or
3-thienyl. Preferably, R.sub.6 is H or fluoro. Preferably, R.sub.7
is H or fluoro.
[0043] Particularly preferred compounds of formula (I) which are of
special interest as agents useful in the treatment and/or
prophylaxis of conditions which are characterised by
overstimulation of the Tachykinin receptors, in particular NK.sub.3
and NK.sub.2, are: [0044]
3-[4-(2-Hydroxy-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinol-
ine-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0045]
6-Fluoro-3-{4-[2-(2-hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-ylmethyl}-2--
phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide;
[0046] (S)
3-[4-(2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-qui-
noline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0047] (R)
3-[4-(2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-quinolin-
e-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0048]
6-Fluoro-3-[4-(3-hydroxy-propyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-
-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0049]
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-thiophen-2-yl-q-
uinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0050]
6-Fluoro-3-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline--
4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0051]
3-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4--
carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0052]
6-Fluoro-3-(2-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide; [0053]
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-phenyl-qu-
inoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide; [0054]
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen--
2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide;
and [0055]
3-[4-(3-Hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2--
yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide.
[0056] The compounds of formula (I) may have at least one
asymmetric centre- for example the carbon atom labelled with an
asterisk (*) in the compound of formula (I) -- and therefore may
exist in more than one stereoisomeric form. The invention extends
to all such stereoisomeric forms and to mixtures thereof, including
racemates. In particular, the invention includes compounds wherein
the asterisked carbon atom in formula (I) has the stereochemistry
shown in formula (Ib): ##STR4## wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.5, R.sub.6, and R.sub.7 are as defined in relation to formula
(I), and X represents the moiety ##STR5##
[0057] The compounds of formula (I) or their salts or solvates are
preferably in pharmaceutically acceptable or substantially pure
form. By pharmaceutically acceptable form is meant, inter alia,
having a pharmaceutically acceptable level of purity excluding
normal pharmaceutical additives such as diluents and carriers, and
including no material considered toxic at normal dosage levels.
[0058] A substantially pure form will generally contain at least
50% (excluding normal pharmaceutical additives), preferably 75%,
more preferably 90% and still more preferably 95% of the compound
of formula (I) or its salt or solvate.
[0059] One preferred pharmaceutically acceptable form is the
crystalline form, including such form in pharmaceutical
composition. In the case of salts and solvates the additional ionic
and solvent moieties must also be non-toxic.
[0060] Suitable salts are pharmaceutically acceptable salts.
[0061] Suitable pharmaceutically acceptable salts include the acid
addition salts with the conventional pharmaceutical acids, for
example maleic, hydrochloric, hydrobromic, phosphoric, acetic,
fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic,
benzoic, ascorbic and methanesulphonic.
[0062] Suitable pharmaceutically acceptable salts include salts of
acidic moieties of the compounds of formula (I) when they are
present, for example salts of carboxy groups or phenolic hydroxy
groups.
[0063] Suitable salts of acidic moieties include metal salts, such
as for example aluminium, alkali metal salts such as lithium,
sodium or potassium, alkaline earth metal salts such as calcium or
magnesium and ammonium or substituted ammonium salts, for example
those with lower alkylamines such as triethylamine, hydroxy
alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine
or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as
bicyclohexylamine, or with procaine, dibenzylpiperidine,
N-benzyl-.quadrature.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases
of the pyridine type such as pyridine, collidine, quinine or
quinoline.
[0064] Suitable solvates are pharmaceutically acceptable
solvates.
[0065] Suitable pharmaceutically acceptable solvates include
hydrates.
[0066] The term `alkyl` (unless specified to the contrary) when
used alone or when forming part of other groups (such as the
`alkoxy` group) includes straight- or branched-chain alkyl groups
containing 1 to 12, preferably 1-6 carbon atoms, examples include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl
group.
[0067] The term `cycloalkyl` (unless specified to the contrary)
when used alone or when forming part of other groups (such as the
`cycloalkylalkyl` group) includes cyclic saturated or unsaturated
carbon rings including 3-12, preferably 3-8 carbon ring members.
Examples include cyclopropyl, cyclobutyl, cyclohexyl,
cyclooctyl.
[0068] The term `alkenyl` (unless specified to the contrary) when
used alone or when forming part of other groups includes straight-
or branched-unsaturated carbon chains including at least one double
C.dbd.C bond and containing 2-12, preferably 2-6 carbon atoms.
[0069] The term `carbocyclic` refers to cycloalkyl and aryl
rings.
[0070] The term `aryl` includes phenyl and naphthyl, preferably
phenyl which unless specified to the contrary optionally comprise
up to five, preferably up to three substituents selected from
halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy,
amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,
alkylcarbonyloxy, or alkylcarbonyl groups.
[0071] The term `aromatic heterocyclic group` includes groups
comprising aromatic heterocyclic rings containing from 5 to 12 ring
atoms, suitably 5 or 6, and comprising up to four hetero-atoms in
the or each ring selected from S, O or N.
[0072] Composite terms such as `alkylcarboxy`, `cycloalkylalkyl`
and so forth refer to components of a compound which include two
interlinked groups, with the group named latterly in the term being
the linking group, so that `alkylcarboxy` means (alkyl)-COO-whilst
`cycloalkylalkyl` means (cycloalkyl)-(alkyl)-.
[0073] Unless specified to the contrary, suitable substituents for
any heterocyclic group includes up to 4 substituents selected from
the group consisting of: alkyl, alkoxy, aryl and halogen or any two
substituents on adjacent carbon atoms, together with the carbon
atoms to which they are attached, may form an aryl group,
preferably a benzene ring, and wherein the carbon atoms of the aryl
group represented by the said two substituents may themselves be
substituted or unsubstituted.
[0074] It will be understood that, unless otherwise specified,
groups and substituents forming part of a compound in accordance
with the invention are unsubstituted.
[0075] When used herein the term "halogen" or "halo" refers to
fluorine, chlorine, bromine and iodine, preferably fluorine,
chlorine or bromine.
[0076] When used herein the term "acyl" includes residues of acids,
in particular a residue of a carboxylic acid such as an alkyl- or
aryl-carbonyl group.
[0077] The invention also provides in one aspect a process for the
preparation of a compound of formula (I), or a salt thereof and/or
a solvate thereof, which process comprises reacting a compound of
formula (II) or an active derivative thereof: ##STR6##
[0078] wherein R'.sub.6, R'.sub.7, R'.sub.5 and X' are R.sub.6,
R.sub.7, R.sub.5 and X respectively as hereinbefore defined in
relation to formula (I) or (Ib), or a group convertible to R.sub.6,
R.sub.7, R.sub.5 and X respectively; with a compound of formula
(III): ##STR7##
[0079] wherein R'.sup.1, R'.sub.2, and R'.sub.3 are R.sub.1,
R.sub.2, and R.sub.3 as defined for formula (I) or a group or atom
convertible to R.sub.1, R.sub.2, and R.sub.3 respectively; to form
a compound of formula (Ic): ##STR8## wherein R'.sub.1, R'.sub.2,
R'.sub.3, X', R'.sub.5, R'.sub.6 and R'.sub.7 are as defined above,
and thereafter carrying out one or more of the following optional
steps: (i) converting any one of R'.sub.1, R'.sub.2, R'.sub.3, X',
R'.sub.5, R'.sub.6 and R'.sub.7 to R.sub.1, R.sub.2, R.sub.3, X,
R.sub.5, R.sub.6 and R.sub.7 respectively as required, to obtain a
compound of formula (I); (ii) converting a compound of formula (I)
into another compound of formula (I); and (iii) preparing a salt of
the compound of formula (I) and/or a solvate thereof.
[0080] Suitable groups convertible into other groups include
protected forms of said groups.
[0081] Suitably R'.sub.1, R'.sub.2, R'.sub.3, X', R'.sub.5,
R'.sub.6 and R'.sub.7 each represents R.sub.1, R.sub.2, R.sub.3, X,
R.sub.5, R.sub.6 and R.sub.7 respectively or a protected form
thereof.
[0082] It is favoured if the compound of formula (II) is present as
an active derivative.
[0083] A suitable active derivative of a compound of formula (II)
is a transient activated form of the compound of formula (II) or a
derivative wherein the carboxy group of the compound of formula
(II) has been replaced by a different group or atom, for example by
an acyl halide, preferably a chloride, or an acylazide or a
carboxylic acid anhydride.
[0084] Other suitable active derivatives include: a mixed anhydride
formed between the carboxyl moiety of the compound of formula (II)
and an alkyl chloroformate; an activated ester, such as a
cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester,
p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester,
pentachlorophenyl ester, pentafluorophenyl ester,
N-hydroxy-phtalimido ester, N-hydroxypiperidine ester,
N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester;
alternatively, the carboxy group of the compound of formula (II)
may be activated using a carbodiimide or
N,N'-carbonyldiimidazole.
[0085] The reaction between the compound of formula (II) or the
active derivative thereof and the compound of formula (III) is
carried out under the appropriate conventional conditions for the
particular compounds chosen. Generally, when the compound of
formula (II) is present as an active derivative the reaction is
carried out using the same solvent and conditions as used to
prepare the active derivative, preferably the active derivative is
prepared in situ prior to forming the compound of formula (Ic) and
thereafter the compound of formula (I) or a salt thereof and/or a
solvate thereof is prepared.
[0086] For example, the reaction between an active derivative of
the compound of formula (II) and the compound of formula (III) may
be carried out:
[0087] (a) by first preparing an acid chloride and then coupling
said chloride with the compound of formula (III) in the presence of
an inorganic or organic base in a suitable aprotic solvent such as
dimethylformamide (DMF) at a temperature in a range from -70 to
50.degree. C. (preferably in a range from -10 to 20.degree. C.);
or
[0088] (b) by treating the compound of formula (II) with a compound
of formula (III) in the presence of a suitable condensing agent,
such as for example N,N'-carbonyl diimidazole (CDI) or a
carbodiimide such as dicyclohexylcarbodiimide (DCC) or
N-dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the
presence of N-hydroxybenzotriazole (HOBT) to maximise yields and
avoid racemization processes (see Synthesis, 453, 1972), or
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate
(HBTU), in an aprotic solvent, such as a mixture of acetonitrile
(MeCN) and tetrahydrofuran (THF), for example a mixture in a volume
ratio of from 1:9 to 7:3 (MeCN:THF), at any temperature providing a
suitable rate of formation of the required product, such as a
temperature in the range of from -70 to 50.degree. C., preferably
in a range of from -10 to 25.degree. C., for example at 0.degree.
C.
[0089] A preferred reaction is set out in Scheme 1 shown below:
##STR9## wherein R'.sub.1, R'.sub.2, R'.sub.3, X', R'.sub.5,
R'.sub.6 and R'.sub.7 are as defined above.
[0090] In the case in which the corresponding alkyl (such as methyl
or ethyl) ester of compound (II) is utilised, an hydrolysis to
compound (II) is required before conversion to compound (Ic) in
Scheme 1. Such hydrolysis can be carried out under acidic
conditions, such 10-36% hydrochloric acid at a temperature in the
range between 30 and 100.degree. C.
[0091] It will be appreciated that a compound of formula (Ic) may
be converted to a compound of formula (I), or one compound of
formula (I) may be converted to another compound of formula (I) by
interconversion of suitable substituents. Thus, certain compounds
of formula (I) and (Ic) are useful intermediates in forming other
compounds of the present invention.
[0092] Accordingly, in a further aspect the invention provides a
process for preparing a compound of formula (I), or a salt thereof
and/or a solvate thereof, which process comprises converting a
compound of the above defined formula (Ic) wherein at least one of
R'.sup.1, R'.sub.2, R'.sub.3, X', R'.sub.5, R'.sub.6 and R'.sub.7
is not R.sub.1, R.sub.2, R.sub.3, X, R.sub.5, R.sub.6 or R.sub.7
respectively, thereby to provide a compound of formula (I); and
thereafter, as required, carrying out one or more of the following
optional steps: [0093] (i) converting a compound of formula (I)
into another compound of formula (I); and [0094] (ii) preparing a
salt of the compound of formula (I) and/or a solvate thereof.
[0095] Suitably, in the compound of formula (Ic) the variables
R'.sub.1, R'.sub.2, R'.sub.3, X', R'.sub.5, R'.sub.6 and R'.sub.7
are R.sub.1, R.sub.2, R.sub.3, X, R.sub.5, R.sub.6 and R.sub.7
respectively or they are protected forms thereof.
[0096] The above mentioned conversions, protections and
deprotections are carried out using the appropriate conventional
reagents and conditions and are further discussed below.
[0097] A chiral compound of formula (III) wherein R.sub.2 is a
C.sub.5 or C.sub.7 cycloalkyl group, R.sub.3 is methyl and R.sub.1
is H are described in J. Org. Chem. (1996), 61 (12), 4130-4135. A
chiral compound of formula (III) wherein R.sub.2 is phenyl, R.sub.3
is isopropyl and R.sub.1 is H is a known compound described in for
example Tetrahedron Lett. (1994), 35(22), 3745-6.
[0098] The compounds of formula (III) are known commercially
available compounds or they can be prepared from known compounds by
known methods, or methods analogous to those used to prepare known
compounds, for example the methods described in Liebigs Ann. der
Chemie, (1936), 523, 199.
[0099] In some embodiments of the invention, a compound of formula
(ID or the corresponding alkyl (such as methyl or ethyl) ester is
prepared by reacting a compound of formula (IV) or the
corresponding alkyl (such as methyl or ethyl) ester: ##STR10##
[0100] wherein R'.sub.6, R'.sub.7 and R'.sub.5 are as defined above
and L.sub.1 represents a halogen atom such as a bromine atom, with
a compound of formula (V): ##STR11##
[0101] wherein R.sub.4 and R.sub.8 are as defined in relation to
formula (I) or a protected form thereof.
[0102] Suitably, reaction between the compounds of formulae (IV) or
the corresponding alkyl (such as methyl or ethyl) ester and (V) is
carried out under conventional amination conditions, for example
when L.sub.1 is a bromine atom then the reaction is conveniently
carried out in an aprotic solvent, such as tetrahydrofuran or
dimethylformamide at any temperature providing a suitable rate of
formation of the required product, usually at ambient temperature;
preferably the reaction is carried out in the presence of
triethylamine (TEA) or K.sub.2CO.sub.3.
[0103] The compounds of formula (V) are known, commercially
available compounds or they can be prepared using methods analogous
to those used to prepare known compounds; for example the methods
described in the Chemistry of the Amino Group, Patais (Ed.),
Interscience, New York 1968; Advanced Organic Chemistry, March J,
John Wiley & Sons, New York, 1992; J. Heterocyclic Chem.
(1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett.
(1997), 7, 555, or Protective Groups in Organic Synthesis (second
edition), Wiley Interscience, (1991) or other methods mentioned
herein.
[0104] A compound of formula (IV) or the corresponding alkyl (such
as methyl or ethyl) ester may be prepared by appropriate
halogenation of a compound of formula (VI) or the corresponding
alkyl (such as methyl or ethyl) ester: ##STR12## wherein R'.sub.6,
R'.sub.7 and R'.sub.5 are as defined above in relation to formula
(II).
[0105] Suitable halogenation reagents are conventional reagents
depending upon the nature of the halogen atom required, for example
when L.sub.1 is bromine a preferred halogenation reagent is
N-bromosuccinimide (NBS).
[0106] The halogenation of the compound of formula (VI) or the
corresponding alkyl (such as methyl or ethyl) ester is suitably
carried out under conventional conditions, for example bromination
is carried out by treatment with NBS in an inert solvent, such as
carbon tetrachloride CCl.sub.4, or 1,2-dichloroethane or
CH.sub.3CN, at any temperature providing a suitable rate of
formation of the required product, suitably at an elevated
temperature such as a temperature in the range of 60.degree. C. to
100.degree. C., for example 80.degree. C.; preferably the reaction
is carried out in the presence of a catalytic amount of benzoyl
peroxide.
[0107] A compound of formula (VI) is conveniently prepared by
reacting a compound of formula (VII): ##STR13##
[0108] wherein R'.sub.6 and R'.sub.7 are as defined in relation to
formula (II), with a compound of formula (XIII):
R.sub.5'--CO--CH.sub.2--Me (XIII)
[0109] wherein R'.sub.5 is as defined in relation to formula
(II).
[0110] The reaction between the compounds of formula (VII) and
(XIII) is conveniently carried out using Pfitzinger reaction
conditions (see for example J. Prakt. Chem. 33, 100 (1886), J.
Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem.
Rev. 35, 152 (1944)). For example in an alkanolic solvent such as
ethanol, at any temperature providing a suitable rate of formation
of the required product, but generally at an elevated temperature,
such as the reflux temperature of the solvent, and preferably in
the presence of a base such as potassium hydroxide or potassium
tert-butoxide. The Pfitzinger reaction may also be carried out in
presence of an acid, such as acetic acid or hydrochloric acid, at a
temperature providing a suitable rate of formation of the required
product, but generally at an elevated temperature, as described in
J. Med. Chem. 38, 906 (1995).
[0111] The compounds of formula (VII) are known compounds or they
are prepared according to methods used to prepare known compounds
for example those disclosed in J. Org. Chem. 21, 171 (1955); J.
Org. Chem. 21, 169 (1955).
[0112] Alternatively a compound of formula (VI) may be conveniently
prepared by reacting a compound of formula (XIV) ##STR14##
[0113] wherein R'.sub.6 and R'.sub.7 are as defined in relation to
formula (II), with a compound of formula (XV): R.sub.5--CHO
(XV)
[0114] wherein R.sub.15 is as defined in relation to formula (II)
in presence of oxobutyric acid.
[0115] The reaction between the compounds of formula (XIV) and (XV)
is conveniently carried out using Doebner reaction conditions (see
for example Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944);
J. Chem. Soc. B, 1969, 805), for example in an alcoholic solvent
such as ethanol, at any temperature providing a suitable rate of
formation of the required product, but generally at an elevated
temperature, such as the reflux temperature of the solvent.
[0116] The compounds of formula (XIV) and (XV) are known compounds
or they are prepared according to methods used to prepare known
compounds for example as described in Vogel's Textbook of Practical
Organic Chemistry.
[0117] In some alternative embodiments of the invention, a compound
of formula (II) is prepared by reacting a compound of formula (VII)
as defined above with a compound of formula (VIII):
R.sub.5'--CO--CH.sub.2--CH.sub.2-T.sub.5 (VIII) wherein R.sub.15 is
as defined in relation to formula (II), and T.sub.5 is a group
##STR15## where Y is a protecting group such as a benzyl group,
particularly a protecting group which is stable in basic conditions
such as a terbutoxycarbonyl group; and thereafter as required
removing any protecting group, for example by dehydrogenation,
and/or converting any T.sub.5 group to: ##STR16##
[0118] The reaction between the compounds of formula (VII) and
(VIII) is conveniently carried out using Pfitzinger reaction
conditions (see for example J. Prakt. Chem. 33, 100 (1886), J.
Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem.
Rev. 35, 152 (1944)), for example in an alkanolic solvent such as
ethanol, at any temperature providing a suitable rate of formation
of the required product, but generally at an elevated temperature,
such as the reflux temperature of the solvent, and preferably in
the presence of a base such as potassium hydroxide or potassium
tert-butoxide.
[0119] Protected forms of, ##STR17##
[0120] will vary according to the particular nature of the group
being protected but will be chosen in accordance with normal
chemical practice.
[0121] Groups convertible to, ##STR18## include groups dictated by
conventional chemical practice to be required and to be
appropriate, depending upon the specific nature of the group under
consideration.
[0122] Suitable deprotection methods for deprotecting protected
forms of ##STR19## and conversion methods for converting T.sub.5
to, ##STR20## will be those used conventionally in the art
depending upon the particular groups under consideration with
reference to standard texts such as Greene, T. W. and Wuts, P. G.
M. Protective Groups in Organic Synthesis, John Wiley & Sons
Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting
groups. George Thieme Verlag, New York, 1994 and Chemistry of the
Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced
Organic Chemistry, March J, John Wiley & Sons, New York,
1992.
[0123] A compound of formula (VIII) is prepared from a compound of
formula (IX): R.sub.5'--CO--CH.sub.2--CH.sub.2--OH (IX)
[0124] wherein R'.sub.5 is as defined in relation to formula (II),
by first halogenating, preferably brominating, or mesylating the
compound of formula (IX) and thereafter reacting the halogenation
or mesylation product so formed with a compound capable of forming
a group T.sub.5 so as to provide the required compound of formula
(VII).
[0125] When T.sub.5 is a group, ##STR21##
[0126] a compound capable of forming a group T.sub.5 is a compound
of the above defined formula (V).
[0127] The halogenation of the compound of formula (IX) is suitably
carried out using a conventional halogenation reagent. Mesylation
is conveniently carried out using mesyl chloride in an inert
solvent such as methylene dichloride, at a temperature below room
temperature, such as 0.degree. C., preferably in the presence of
triethylamine.
[0128] The reaction conditions between the compound of formula (IX)
and the compound capable of forming a group T.sub.5 will be those
conventional conditions dictated by the specific nature of the
reactants, for example when the T.sub.5 required is a group,
##STR22## and the required compound capable of forming a group
T.sub.5 is a compound of the above defined formula (V), then the
reaction between the halogenation or mesylation product of the
compound of formula (IX) and the compound of formula (V) is carried
out under analogous conditions to those described for the reaction
between the compounds of formulae (IV) and (V).
[0129] Other compounds capable of forming a group T.sub.5 will
depend upon the particular nature of T.sub.5, but will be those
appropriate compounds dictated by conventional chemical practice
with reference to standard texts such as Chemistry of the Amino
Group, Patais (Ed.), Interscience, New York 1968; and Advanced
Organic Chemistry, March J, John Wiley & Sons, New York,
1992.
[0130] A compound of formula (IX) may be prepared by reacting a
compound of formula (X): ##STR23##
[0131] wherein a is as defined in relation to formula (VIII), with
a lithium salt of formula (XI): R.sub.15Li (XI) wherein R.sub.15 is
as defined in relation to formula (II).
[0132] The reaction between the compounds of formulae (X) and (XI)
can be carried out in an aprotic solvent, such as diethyl-ether at
any temperature providing a suitable rate of formation of the
required product, usually at a low temperature such as in the range
of -10.degree. C. to -30.degree. C., for example -20.degree. C.
[0133] The compounds of formula (VII) are known compounds or they
are prepared according to methods used to prepare known compounds
for example those disclosed in J. Org. Chem. 21, 171 (1955); J.
Org. Chem. 21, 169 (1955).
[0134] The compounds of formula (X) and (XI) are known compounds or
they are prepared according to methods used to prepare known
compounds for example those disclosed by Krow G. R. in Organic
Reactions, Vol 43, page 251, John Wiley & Sons Inc. 1994 (for
the compounds of formula (X)) and Organometallics in Synthesis,
Schlosser M. (Ed), John Wiley & Sons Inc. 1994 (for the
compounds of formula (XI)).
[0135] In another aspect, the present invention provides a process
for the preparation of a compound of formula (I), or a salt thereof
and/or a solvate thereof, which process comprises reacting a
compound of formula (XVI): ##STR24## wherein each of R'.sub.1,
R'.sub.2, R'.sub.3, R'.sub.5, R'.sub.6, and R'.sub.7 is
respectively R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, or
R.sub.7 as defined above or a group convertible to R.sub.1,
R.sub.2, R.sub.3, R.sub.5, R.sub.6, or R.sub.7 respectively as
defined above providing R'.sub.2 is not aromatic in character, and
L.sub.1 represents a halogen atom such as a bromine atom, with a
compound of formula (V) or a protected form thereof or a group
convertible thereto; and thereafter carrying out one or more of the
following optional steps: [0136] (i) converting any one of
R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16 and
R.sub.17 to R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6
and R.sub.7 respectively as required, to obtain a compound of
formula (I); [0137] (ii) converting a compound of formula (I) into
another compound of formula (I); and [0138] (iii) preparing a salt
of the compound of formula (I) and/or a solvate thereof.
[0139] Protected forms of compounds of formula (V) will vary
according to the particular nature of the group being protected but
will be chosen in accordance with normal chemical practice.
[0140] Groups convertible to R.sub.4 include groups dictated by
conventional chemical practice to be required and to be
appropriate, depending upon the specific nature of the R.sub.4
under consideration.
[0141] Suitable deprotection methods for deprotecting protected
forms of R.sub.4 and conversion methods for converting R'.sub.4 to
R.sub.4 will be those used conventionally in the art depending upon
the particular groups under consideration with reference to
standard texts such as Greene, T. W. and Wuts, P. G. M. Protective
Groups in Organic Synthesis, John Wiley & Sons Inc. New York,
1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George
Thieme Verlag, New York, 1994 and Chemistry of the Amino Group,
Patais (Ed.), Interscience, New York 1968; or Advanced Organic
Chemistry, March J, John Wiley & Sons, New York, 1992.
[0142] Suitable groups convertible into other groups include
protected forms of said groups.
[0143] Suitably R'.sub.1, R'.sub.2, R'.sub.3, R'.sub.4, R'.sub.5,
R'.sub.6 and R'.sub.7 each represents R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6 and R.sub.7 respectively or a protected
form thereof.
[0144] Suitable deprotection methods for deprotecting protected
forms of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and
R.sub.7 and conversion methods for converting R'.sub.1, R'.sub.2,
R'.sub.3, R'.sub.4, R'.sub.5, R'.sub.6 and R'.sub.7 to R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7
respectively will be those used conventionally in the art depending
upon the particular groups under consideration with reference to
standard texts such as Greene, T. W. and Wuts, P. G. M. Protective
Groups in Organic Synthesis, John Wiley & Sons Inc. New York,
1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George
Thieme Verlag, New York, 1994 and Chemistry of the Amino Group,
Patais (Ed.), Interscience, New York 1968; or Advanced Organic
Chemistry, March J, John Wiley & Sons, New York, 1992.
[0145] Suitably, reaction between the compounds of formulae (XVI)
and (XVII) is carried out under conventional amination conditions,
for example when L.sub.1 is a bromine atom then the reaction is
conveniently carried out in an aprotic solvent, such as
tetrahydrofuran or dimethylformamide or acetonitrile at any
temperature providing a suitable rate of formation of the required
product, usually at ambient temperature; preferably the reaction is
carried out in the presence of triethylamine (TEA), sodium hydride
or K.sub.2CO.sub.3.
[0146] The compounds of formula (XVII) are known, commercially
available compounds or they can be prepared using methods analogous
to those used to prepare known compounds; for example the methods
described in the Chemistry of the Amino Group, Patais (Ed.),
Interscience, New York 1968; Advanced Organic Chemistry, March J,
John Wiley & Sons, New York, 1992; J. Heterocyclic Chem.
(1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett.
(1997), 7, 555, or Protective Groups in Organic Synthesis (second
edition), Wiley Interscience, (1991) or other methods mentioned
herein.
[0147] A compound of formula (XVI) is prepared by appropriate
halogenation of a compound of formula (XVIII): ##STR25##
[0148] wherein R'.sub.1, R'.sub.2, R'.sub.3, R'.sub.5, R'.sub.6,
and R'.sub.7 are as defined above in relation to formula (XVI).
[0149] Suitable halogenation reagents are conventional reagents
depending upon the nature of the halogen atom required, for example
when L.sub.1 is bromine a preferred halogenation reagent is
N-bromosuccinimide (NBS).
[0150] The halogenation of the compound of formula (XVIII) is
carried out under conventional conditions, for example bromination
is carried out by treatment with NBS in an inert solvent, such as
carbon tetrachloride CCl.sub.4, or 1,2-dichloroethane or
CH.sub.3CN, at any temperature providing a suitable rate of
formation of the required product, suitably at an elevated
temperature such as a temperature in the range of 60.degree. C. to
100.degree. C., for example 80.degree. C.; preferably the reaction
is carried out in the presence of a catalytic amount of benzoyl
peroxide.
[0151] Suitably, the compound of formula (XVIII) may be prepared by
reacting a compound of formula (VI) as defined above or an active
derivative thereof with a compound of formula (III) as defined
above wherein R'.sub.2 is not aromatic in character.
[0152] It is favoured if the compound of formula (VI) is present in
the reaction mix as an active derivative, as hereinbefore
described.
[0153] The reaction between the compound of formula (VI) or the
active derivative thereof and the compound of formula (III) is
carried out under the appropriate conventional conditions for the
particular compounds chosen. Generally, when the compound of
formula (VI) is present as an active derivative the reaction is
carried out using the same solvent and conditions as used to
prepare the active derivative, preferably the active derivative is
prepared in situ prior to forming the compound of formula
(XVIII).
[0154] For example, the reaction between an active derivative of
the compound of formula (VI) and the compound of formula (III) may
be carried out:
[0155] (a) by first preparing an acid chloride and then coupling
said chloride with the compound of formula (III) in the presence of
an inorganic or organic base in a suitable aprotic solvent such as
methylene dichloride or tetrahydrofuran at a temperature in a range
from -70 to 50.degree. C. (preferably in a range from 20.degree. C.
to reflux temperature); or
[0156] (b) by treating the compound of formula (VI) with a compound
of formula (III) in the presence of a suitable condensing agent,
such as for example N,N'-carbonyl diimidazole (CDI) or a
carbodiimide such as dicyclohexylcarbodiimide (DCC) or
N-dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the
presence of N-hydroxybenzotriazole (HOBT) to maximise yields and
avoid racemization processes (see Synthesis, 453, 1972), or
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate
(HBTU), in an aprotic solvent, such as a mixture of acetonitrile
(MeCN) and tetrahydrofuran (THF), for example a mixture in a volume
ratio of from 1:9 to 7:3 (MeCN:THF), at any temperature providing a
suitable rate of formation of the required product, such as a
temperature in the range of from -70 to 50.degree. C., preferably
in a range of from -10 to 25.degree. C., for example at 0.degree.
C.
[0157] A preferred reaction is set out in Scheme 2 shown below:
##STR26##
[0158] In the case in which the corresponding alkyl (such as methyl
or ethyl) ester of compounds (VI) is utilised, a hydrolysis is
required before conversion to compound (XVIII) in Scheme 2. Such
hydrolysis can be carried out under acidic conditions, such 10-36%
hydrochloric acid at a temperature in the range between 30 and
100.degree. C.
[0159] As hereinbefore mentioned, the compounds of formula (I) may
exist in more than one stereoisomeric form--and the process of the
invention may produce racemates as well as enantiomerically pure
forms. Accordingly, a pure enantiomer of a compound of formula (I)
can be obtained by reacting a compound of the above defined formula
(II) with an appropriate enantiomerically pure primary amine of
formula (IIIa) or (IIIc): ##STR27##
[0160] wherein R'.sub.1, R'.sub.2 and R'.sub.3 are as defined
above, to obtain a compound of formula (I'c) or (I'c):
##STR28##
[0161] wherein R'.sub.1, R'.sub.2, R'.sub.3, X', R'.sub.5,
R'.sub.6, and R'.sub.7 are as defined above.
[0162] Compounds of formula (I'a) or (I'c) may subsequently be
converted to compounds of formula (Ia) or (Ic) by the methods of
conversion mentioned before: ##STR29##
[0163] wherein R.sub.1, R.sub.2, R.sub.3, X, R.sub.5, R.sub.6, and
R.sub.7 are as defined above.
[0164] Suitably, in the above mentioned compounds of formulae (Ia),
(Ic), (I'a), (I'c), (IIIa) and (IIIc) R.sub.1 represents
hydrogen.
[0165] An alternative method for separating optical isomers is to
use conventional, fractional separation methods in particular
fractional crystallization methods. Thus, a pure enantiomer of a
compound of formula (I) is obtained by fractional crystallisation
of a diastereomeric salt formed by reaction of the racemic compound
of formula (I) with an optically active strong acid resolving
agent, such as camphorsulphonic acid, tartaric acid,
O,O'-di-p-toluoyltartaric acid or mandelic acid, in an appropriate
alcoholic solvent, such as ethanol or methanol, or in a ketonic
solvent, such as acetone. The salt formation process should be
conducted at a temperature between 20.degree. C. and 80.degree. C.,
preferably at 50.degree. C.
[0166] A suitable conversion of one compound of formula (I) into a
further compound of formula (I) involves converting one group X
into another group X by for example:
(i) converting a ketal into a ketone, by such as mild acidic
hydrolysis, using for example dilute hydrochloric acid;
(ii) reducing a ketone to a hydroxy group by use of a borohydride
reducing agent;
(iii) converting a carboxylic ester group into a carboxyl group
using basic hydrolysis; and/or
(iv) reducing a carboxylic ester group to a hydroxymethyl group, by
use of a borohydride reducing agent.
[0167] As indicated above, where necessary, the conversion of any
group R'.sub.1, R'.sub.2, R'.sub.3, X', R'.sub.5, R'.sub.6, and
R'.sub.7 into R.sub.1, R.sub.2, R.sub.3, X, R.sub.5, R.sub.6, and
R.sub.7 which as stated above are usually protected forms of
R.sub.1, R.sub.2, R.sub.3, X, R.sub.5, R.sub.6, or R.sub.7 may be
carried out using appropriate conventional conditions such as the
appropriate deprotection procedure.
[0168] It will be appreciated that in any of the above mentioned
reactions any reactive group in the substrate molecule may be
protected and deprotected according to conventional chemical
practice, for example as described by Greene, T. W. and Wuts, P. G.
M. Protective Groups in Organic Synthesis, John Wiley & Sons
Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting
groups. George Thieme Verlag, New York, 1994.
[0169] Suitable protecting groups in any of the above mentioned
reactions are those used conventionally in the art. Thus, for
example suitable hydroxy protecting groups include benzyl or
trialkylsilyl groups.
[0170] The methods of formation and removal of such protecting
groups are those conventional methods appropriate to the molecule
being protected. Thus for example a benzyloxy group may be prepared
by treatment of the appropriate compound with a benzyl halide, such
as benzyl bromide, and thereafter, if required, the benzyl group
may be conveniently removed using catalytic hydrogenation or a mild
ether cleavage reagent such as trimethylsilyl iodide or boron
tribromide.
[0171] As indicated above, the compounds of formula (I) have useful
pharmaceutical properties.
[0172] Accordingly the present invention also provides a compound
of formula (I), or a pharmaceutically acceptable salt or solvate
thereof, for use as an active therapeutic substance.
[0173] In particular, the present invention also provides a
compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof, for the treatment or prophylaxis of the Primary
and Secondary Conditions.
[0174] The present invention further provides a pharmaceutical
composition comprising a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable carrier.
[0175] The present invention also provides the use of a compound of
formula (I), or a pharmaceutically acceptable salt or solvate
thereof, in the manufacture of a medicament for the treatment of
the Primary and Secondary Conditions.
[0176] As mentioned above the Primary conditions include
respiratory diseases, such as chronic obstructive pulmonary disease
(COPD), asthma, airway hyperreactivity, cough; inflammatory
diseases such as inflammatory bowel disease, psoriasis, fibrositis,
osteoarthritis, rheumatoid arthritis and inflammatory pain;
neurogenic inflammation or peripheral neuropathy, allergies such as
eczema and rhinitis; ophthalmic diseases such as ocular
inflammation, conjunctivitis, vernal conjuctivitis and the like;
cutaneous diseases, skin disorders and itch, such as cutaneous
wheal and flare, contact dermatitis, atopic dermatitis, urticaria
and other eczematoid dermatitis; adverse immunological reactions
such as rejection of transplanted tissues and disorders related to
immune enhancement or suppression such as systemic lupus
erythematosis; gastrointestinal (GI) disorders and diseases of the
GI tract such as disorders associated with the neuronal control of
viscera such as ulcerative colitis, Crohn's disease, irritable
bowel syndrome (IBS), gastro-exophageous reflex disease (GERD);
urinary incontinence and disorders of the bladder function; renal
disorders; increased blood pressure, proteinuria, coagulopathy and
peripheral and cerebral oedema following pre-eclampsia in
pregnancies.
[0177] As mentioned above, the Secondary conditions include
disorders of the central nervous system such as anxiety,
depression, psychosis and schizophrenia; neurodegenerative
disorders such as AIDS related dementia, senile dementia of the
Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's
disease, Parkinson's disease, movement disorders and convulsive
disorders (for example epilepsy); demyelinating diseases such as
multiple sclerosis and amyotrophic lateral sclerosis and other
neuropathological disorders such as diabetic neuropathy, AIDS
related neuropathy, chemotherapy-induced neuropathy and neuralgia;
addiction disorders such as alcoholism; stress related somatic
disorders; reflex sympathetic dystrophy such as shoulder/hand
syndrome; dysthymic disorders; eating disorders (such as food
intake disease); fibrosing and collagen diseases such as
scleroderma and eosinophilic fascioliasis; disorders of the blood
flow caused by vasodilatation and vasospastic diseases such as
angina, migraine and Reynaud's disease and pain or nociception, for
example, that is attributable to or associated with any of the
foregoing conditions especially the transmission of pain in
migraine.
[0178] Such a medicament, and a composition of this invention, may
be prepared by admixture of a compound of the invention with an
appropriate carrier. It may contain a diluent, binder, filler,
disintegrant, flavouring agent, colouring agent, lubricant or
preservative in conventional manner.
[0179] These conventional excipients may be employed for example as
in the preparation of compositions of known agents for treating the
conditions.
[0180] Preferably, a pharmaceutical composition of the invention is
in unit dosage form and in a form adapted for use in the medical or
veterinarial fields. For example, such preparations may be in a
pack form accompanied by written or printed instructions for use as
an agent in the treatment of the conditions.
[0181] The suitable dosage range for the compounds of the invention
depends on the compound to be employed and on the condition of the
patient. It will also depend, inter alia, upon the relation of
potency to absorbability and the frequency and route of
administration.
[0182] The compound or composition of the invention may be
formulated for administration by any route, and is preferably in
unit dosage form or in a form that a human patient may administer
to himself in a single dosage. Advantageously, the composition is
suitable for oral, rectal, topical, parenteral, intravenous or
intramuscular administration. Preparations may be designed to give
slow release of the active ingredient.
[0183] Compositions may, for example, be in the form of tablets,
capsules, sachets, vials, powders, granules, lozenges,
reconstitutable powders, or liquid preparations, for example
solutions or suspensions, or suppositories.
[0184] The compositions, for example those suitable for oral
administration, may contain conventional excipients such as binding
agents, for example syrup, acacia, gelatine, sorbitol, tragacanth,
or polyvinylpyrrolidone; fillers, for example lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricants, for example magnesium stearate; disintegrants, for
example starch, polyvinyl-pyrrolidone, sodium starch glycollate or
microcrystalline cellulose; or pharmaceutically acceptable setting
agents such as sodium lauryl sulphate.
[0185] Solid compositions may be obtained by conventional methods
of blending, filling, tabletting or the like. Repeated blending
operations may be used to distribute the active agent throughout
those compositions employing large quantities of fillers. When the
composition is in the form of a tablet, powder, or lozenge, any
carrier suitable for formulating solid pharmaceutical compositions
may be used, examples being magnesium stearate, starch, glucose,
lactose, sucrose, rice flour and chalk. Tablets may be coated
according to methods well known in normal pharmaceutical practice,
in particular with an enteric coating. The composition may also be
in the form of an ingestible capsule, for example of gelatine
containing the compound, if desired with a carrier or other
excipients.
[0186] Compositions for oral administration as liquids may be in
the form of, for example, emulsions, syrups, or elixirs, or may be
presented as a dry product for reconstitution with water or other
suitable vehicle before use. Such liquid compositions may contain
conventional additives such as suspending agents, for example
sorbitol, syrup, methyl cellulose, gelatine, hydroxyethylcellulose,
carboxymethylcellulose, aluminium stearate gel, hydrogenated edible
fats; emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia; aqueous or non-aqueous vehicles, which
include edible oils, for example almond oil, fractionated coconut
oil, oily esters, for example esters of glycerine, or propylene
glycol, or ethyl alcohol, glycerine, water or normal saline;
preservatives, for example methyl or propyl p-hydroxybenzoate or
sorbic acid; and if desired conventional flavouring or colouring
agents.
[0187] The compounds of this invention may also be administered by
a non-oral route. In accordance with routine pharmaceutical
procedure, the compositions may be formulated, for example for
rectal administration as a suppository. They may also be formulated
for presentation in an injectable form in an aqueous or non-aqueous
solution, suspension or emulsion in a pharmaceutically acceptable
liquid, e.g. sterile pyrogen-free water or a parenterally
acceptable oil or a mixture of liquids. The liquid may contain
bacteriostatic agents, anti-oxidants or other preservatives,
buffers or solutes to render the solution isotonic with the blood,
thickening agents, suspending agents or other pharmaceutically
acceptable additives. Such forms will be presented in unit dose
form such as ampoules or disposable injection devices or in
multi-dose forms such as a bottle
from which the appropriate dose may be withdrawn or a solid form or
concentrate which can be used to prepare an injectable
formulation.
[0188] The compounds of this invention may also be administered by
inhalation, via the nasal or oral routes. Such administration can
be carried out with a spray formulation comprising a compound of
the invention and a suitable carrier, optionally suspended in, for
example, a hydrocarbon propellant.
[0189] Preferred spray formulations comprise micronised compound
particles in combination with a surfactant, solvent or a dispersing
agent to prevent the sedimentation of suspended particles.
Preferably, the compound particle size is from about 2 to 10
microns.
[0190] A further mode of administration of the compounds of the
invention comprises transdermal delivery utilising a skin-patch
formulation. A preferred formulation comprises a compound of the
invention dispersed in a pressure sensitive adhesive which adheres
to the skin, thereby permitting the compound to diffuse from the
adhesive through the skin for delivery to the patient. For a
constant rate of percutaneous absorption, pressure sensitive
adhesives known in the art such as natural rubber or silicone can
be used.
[0191] As mentioned above, the effective dose of compound depends
on the particular compound employed, the condition of the patient
and on the frequency and route of administration. A unit dose will
generally contain from 20 to 1000 mg and preferably will contain
from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350,
400, 450, or 500 mg. The composition may be administered once or
more times a day for example 2, 3 or 4 times daily, and the total
daily dose for a 70 kg adult will normally be in the range 100 to
3000 mg. Alternatively the unit dose will contain from 2 to 20 mg
of active ingredient and be administered in multiples, if desired,
to give the preceding daily dose.
[0192] No unacceptable toxicological effects are expected with
compounds of the invention when administered in accordance with the
invention.
[0193] The present invention also provides a method for the
treatment and/or prophylaxis of the Primary and Secondary
Conditions in mammals, particularly humans, which comprises
administering to the mammal in need of such treatment and/or
prophylaxis an effective, non-toxic pharmaceutically acceptable
amount of a compound of formula (I) or a pharmaceutically
acceptable salt or solvate thereof.
[0194] The activity of the compounds of the present invention, as
NK.sub.3 ligands, is determined by their ability to inhibit the
binding of the radiolabelled NK.sub.3 ligands,
[.sup.125I]-[Me-Phe.sup.7]-NKB or [.sup.3H]-Senktide, to guinea-pig
and human NK.sub.3 receptors (Renzetti et al, 1991, Neuropeptide,
18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al,
1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
[0195] The binding assays utilised allow the determination of the
concentration of the individual compound required to reduce by 50%
the [.sup.125I]-[Me-Phe.sup.7]-NKB and [.sup.3H]-Senktide specific
binding to NK.sub.3 receptor in equilibrium conditions (IC50).
[0196] Binding assays provide for each compound tested a mean
IC.sub.50 value of 2-5 separate experiments performed in duplicate
or triplicate. The most potent compounds of the present invention
show IC.sub.50 values in the range 0.1-1000 nM. The
NK.sub.3-antagonist activity of the compounds of the present
invention is determined by their ability to inhibit
senktide-induced contraction of the guinea-pig ileum (Maggi et al,
1990, Br. J. Pharmacol, 101, 996-1000) and rabbit isolated iris
sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14)
and human NK.sub.3 receptors-mediated Ca.sup.++ mobilisation
(Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Guinea-pig
and rabbit in-vitro functional assays provide for each compound
tested a mean K.sub.B value of 3-8 separate experiments, where
K.sub.B is the concentration of the individual compound required to
produce a 2-fold rightward shift in the concentration-response
curve of senktide. Human receptor functional assay allows the
determination of the concentration of the individual compound
required to reduce by 50% (IC.sub.50 values) the Ca.sup.++
mobilisation induced by the agonist NKB. In this assay, the
compounds of the present invention behave as antagonists.
[0197] The activity of the compounds of the present invention, as
NK.sub.2 ligands, is determined by their ability to inhibit the
binding of the radiolabelled NK.sub.2 ligands, [.sup.125I]-NKA or
[.sup.3H]-NKA, to human NK.sub.2 receptors (Aharony et al, 1992,
Neuropeptide, 23, 121-130).
[0198] The binding assays utilised allow the determination of the
concentration of the individual compound required to reduce by 50%
the [.sup.125I]-NKA and [.sup.3H]-NKA specific binding to NK.sub.2
receptor in equilibrium conditions (IC.sub.50).
[0199] Binding assays provide for each compound tested a mean ICs0
value of 2-5 separate experiments performed in duplicate or
triplicate. The most potent compounds of the present invention show
IC.sub.50 values in the range 0.5-1000 nM, such as 1-1000 nM. The
NK.sub.2-antagonist activity of the compounds of the present
invention is determined by their ability to inhibit human NK.sub.2
receptor-mediated Ca.sup.++ mobilisation (Mochizuki et al, 1994, J.
Biol. Chem., 269, 9651-9658). Human receptor functional assay
allows the determination of the concentration of the individual
compound required to reduce by 50% (IC.sub.50 values) the Ca.sup.++
mobilisation induced by the agonist NKA. In this assay, the
compounds of the present invention behave as antagonists.
[0200] The therapeutic potential of the compounds of the present
invention in treating the conditions can be assessed using rodent
disease models.
[0201] As stated above, the compounds of formula (I) are also
considered to be useful as diagnostic tools. Accordingly, the
invention includes a compound of formula (I) for use as diagnostic
tools for assessing the degree to which neurokinin-3 and
neurokinin-2 receptor activity (normal, overactivity or
underactivity) is implicated in a patient's symptoms. Such use
comprises the use of a compound of formula (I) as an antagonist of
said activity, for example including but not restricted to
Tachykinin agonist-induced inositol phosphate turnover or
electrophysiological activation, of a cell sample obtained from a
patient. Comparison of such activity in the presence or absence of
a compound of formula (I), will disclose the degree of NK.sub.3 and
NK.sub.2 receptor involvement in the mediation of agonist effects
in that tissue.
[0202] The following Descriptions illustrate the preparation of the
intermediates, whereas the following Examples illustrate the
preparation of the compounds of the invention.
DESCRIPTIONS AND EXAMPLES
Description 1
3-Methyl-2-phenylquinoline 4-carboxylic acid
[0203] Isatine (40 g, 0.272 mol) is suspended in EtOH (1 1) and KOH
(62.8 g, 1.1 mol). Suspension is stirred for 30 min. Propiophenone
(36.2 cc, 0.272 mol) was added and the reaction was refluxed for 4
h. The reaction was left overnight at room temperature and then
EtOH was evaporated under vacuum. The solid was dissolved in water
(400 ml) and washed with Et.sub.2O. The aqueous phase was acidified
with citric acid (saturated solution) and a solid was obtained. The
solid was filtered by suction, washed with water and dried in oven
to afford the title compound. mp>280.degree. C.
Description 2
((S)-1-Cyclohexyl-ethyl)-3-methyl-2-phenylquinoline-4-carboxamide
[0204] 4-Carboxy-3-methyl-2-phenylquinoline (40 g, 0.152 mol)
prepared as in Description 1, was suspended in CH.sub.2Cl.sub.2
(600 ml) and oxalyl chloride (6.6 ml, 0.311 mol) was added dropwise
at 0.degree. C. under magnetic stirring. After 15 min 2 drops of
DMF were added. The reaction was vigorous with gas evolution. The
mixture was stirred at room temperature until the solid was
completely dissolved (about 2 h). The solution was evaporated. The
crude material was re-dissolved in CH.sub.2Cl.sub.2 (150 ml) and
slowly dropped into a suspension of K.sub.2CO.sub.3 (47 g) and
(S)-1-cyclohexylethyl amine (29 ml, 0.196 mol) in CH.sub.2Cl.sub.2
(250 ml) maintaining the temperature between 10-15.degree. C. The
dark solution was left 1 h at room temperature and 1 h refluxing.
The organic phase was then washed with water, NaOH 1N, brine, dried
over Na.sub.2SO.sub.4 and then evaporated under vacuum. The crude
residue was triturated with EtOAc and filtered to afford the title
compound. mp: 177-180.degree. C.
[0205] C.sub.25H.sub.28N.sub.2O
[0206] MW=372.51
[0207] [.alpha.]D+21.77 (c=0.4 in MeOH).
Description 3
((S)-1-Cyclohexylethyl)-3-bromomethyl-2-phenylquinoline-4-carboxamide
[0208] 3-Methyl-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (9.8 g, 26 mmol; compound prepared
as in Description 2) and N-bromosuccinimmide (9.8 g, 55 mmol) were
suspended in CCl.sub.4 (100 ml) and warmed to incipient reflux.
Dibenzoyl peroxide (about 300 mg) was carefully added dropwise and
the solution was then refluxed for 2 h. The solvent was removed
under vacuum and the residue was re-dissolved in CH.sub.2Cl.sub.2
(200 ml) and filtered. DCM was then evaporated and the residue was
dissolved in EtOAc and washed with a saturated solution of
NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated to give the title compound as a powder, suitable for use
without further purification. mp: 182-184.degree. C.
C.sub.25H.sub.27BrN.sub.2O
[0209] MW=451.41
[0210] [.alpha.].sub.D=-5.76 (c=0.5% in CH.sub.2Cl.sub.2)
Description 4
6,7-Difluoro-3-methyl-2-phenyl-quinoline-4-carboxylic acid
[0211] A solution of 5,6-difluoroisatine (4.68 g; 25.6 mmol)
(prepared as in JACS 1958, 23, 1858) and phenylethylketone (3.40
ml; 25.6 mmol) in glacial acetic acid (150 ml) was stirred for 5
minutes at 105.degree. C. HCl 37% was added (38 ml) and the
reaction mixture was stirred at 105.degree. C. for 24 h. The
reaction was then cooled to room temperature and diluted with water
(400 ml). Filtration and subsequent drying of the precipitate
afforded the title compound as a solid.
Description 5
3-(3-Oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
[0212] A solution of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide (10 g, 22 mmol, prepared as in
Description 3), piperazin-2-one (CAS [5625-67-2]) (3 g, 30 mmol)
and ethyldiisopropylamine (11 ml, 66 mmol) in dry THF (200 ml) was
stirred for 24 h at room temperature. The solvent was evaporated to
dryness in vacuum and the residue was re-dissolved in EtOAc. This
mixture washed with a dilute NaOH solution, with water and dried
over Na.sub.2SO.sub.4. After evaporating to dryness, the residue
was triturated with Et.sub.2O to afford the title compound. Said
compound may be utilised without further purification.
Description 6
General procedure for piperazinone alkylation
[0213] Method A: To a solution of piperazinone derivatives (1 mmol,
compound prepared as in Description 5) in anhydrous DMF (10 ml),
60% NaH (2 mmol, 29 mg) was added at 0.degree. C. The dark solution
obtained was stirred for 10 minutes at 0.degree. C. and then for
additional 20 minutes at room temperature. The solution was
re-cooled at 0.degree. C. and the electrophilic species (1 mmol)
was added.
[0214] The reaction was stirred overnight then poured into a
saturated solution of NaCl and extracted with EtOAc. The organic
phases were dried over Na.sub.2SO.sub.4, filtered and evaporated
under vacuum to give after purification by flash chromatography the
desired compound.
[0215] Method B: A mixture of piperazinone derivatives (0.47 g, 1
mmol, compound prepared as in Description 5), alkylating reagent
(1.2 mmol) and KOH (0.23 g, 4 mmol) in anhydrous DMSO (10 ml), was
stirred for 36 hours at room temperature. The reaction was diluted
with a saturated solution of NaCl and the product was extracted
with DCM. The organic phases were dried over Na.sub.2SO.sub.4,
filtered and evaporated under vacuum; the residue was purificated
by flash chromatography to afford the desired compound.
Description 7
3-Bromomethyl-6,7-difluoro-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
[0216] The compound was prepared according to Descriptions 2 and 3
starting from the compound in Description 4.
Description 8
3-Bromomethyl-6-fluoro-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
[0217] The compound was prepared according to Description 1,
starting from 5-fluoroisatine CAS[443-69-6] and phenylethylketone,
Description 2 and 3.
Description 9
6-Fluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide
[0218] The compound was prepared according to Description 5
starting from the compound of Description 8 and piperazinone
(CAS[5625-67-2]).
Description 10
3-Bromomethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
[0219] The compound was prepared according to Description 1,
starting from 1-thiophen-2-yl-propan-1-one CAS [13679-75-9] and
isatine, Description 2 and 3.
Description 11
3-(3-Oxo-piperazin-1-ylmethyl)-2-thiophen-2-y3-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide
[0220] The compound was prepared according to Description 5
starting from the compound of Description 10 and piperazinone (CAS
[5625-67-2]).
Description 12
3-Bromomethyl-2-thiophen-3-yl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
[0221] The compound was prepared according to Description 1,
starting from 1-thiophen-3-yl-propan-1-one CAS [51179-52-3] and
isatine, Description 2 and 3.
Description 13
4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-6-fluoro-2-phenyl-quinolin-3-ylmeth-
yl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester
[0222] To a suspension of 3-oxo-piperazine-1-carboxylic acid
tert-butyl ester (0.3 g, 1.5 mmol, CAS [76003-29-7]) in DMF/DMSO
2/1 (10 ml), 60% NaH (60 mg, 1.5 mmol) was added at 0.degree. C.
After stirring for 30 minutes a solution of
3-bromomethyl-6-fluoro-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.6 g, 1.3 mmol, prepared according
to Description 8) in DMF (3 ml) was slowly added. The reaction was
stirred for 3 hours at room temperature then poured into a
saturated solution of NaCl. The obtained precipitated was filtered
and purified by flash chromatography to afford the title
compound.
Description 14
Piperazine-1-carboxylic acid tert-butyl ester
[0223] To a solution of piperazine (30 g, 350 mmol) in water (370
ml) and tBuOH (420 ml), a solution of 4N NaOH (70 ml) was added.
The mixture was cooled to 0.degree. C. and then BOC.sub.2O (38 g,
170 mmol) was added dropwise. After stirring at room temperature
for 45 minutes, tBuOH was evaporated under vacuum, the precipitate
(diBOCpiperazine) was filtered and water was extracted with
CH.sub.2Cl.sub.2. After drying over Na.sub.2SO.sub.4 the solvent
was removed under vacuum to afford the title compound as a solid.
C.sub.9H.sub.18N.sub.2O.sub.2
[0224] MW=186.25
Description 15
2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
[0225]
4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethy-
l]-piperazine 1-carboxylic acid tert-butyl ester (2.5 g, 4.5 mmol,
prepared according to Description 5 using piperazine-1-carboxylic
acid tert-butyl ester (Description 14) as nucleophile) was
dissolved in CH.sub.2Cl.sub.2 (60 ml) and TFA (3 ml) was added. The
red solution was stirred at room temperature overnight; then the
solvent and the excess of TFA were removed under vacuum. The
residue was dissolved in H.sub.2O and washed 2 times with
Et.sub.2O. The water extract was made alkaline by addition of 2N
NaOH solution and the product was extracted with EtOAc. The solvent
was evaporated to dryness and the residue was purified by flash
chromatography (eluent CH.sub.2Cl.sub.2: MeOH 93:7) to afford the
title compound.
Description 16
General procedure for synthesis of ureas
[0226] A solution of
2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.3 g, 0.65 mmol, prepared
according to Description 15), isocyanate (0.65 mmol) in CH.sub.3CN
(20 ml) was stirred for 1 hour at room temperature. The solvent was
evaporated under vacuum; the residue was re-dissolved in EtOAc and
washed with a saturated solution of NaCl. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by column chromatography to afford the urea
derivative.
[0227] Example 13 was prepared according to the following general
procedure
[0228] A solution of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide (1 mmol, 0.45 g; compound
prepared as in Description 3), 1.5 mmol of amine and
ethyldiisopropylamine (3 mmol, 0.5 ml) in dry THF (15 ml) was
stirred for 24 h at room temperature. The solvent was evaporated to
dryness in vacuum and the residue was re-dissolved in EtOAc. This
mixture washed with a dilute NaOH solution, with water and dried
over Na.sub.2SO.sub.4. After evaporating to dryness, the residue
was purified by flash chromatography to afford the desired
compound.
Example 1
3-[4-(2-Hydroxy-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoli-
ne-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0229]
3-{3-Oxo-4-[2-(tetrahydropyran-2-yloxy)-ethyl]-piperazin-1-ylmethy-
l}-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexylethyl)-amide (0.12 g, 0.2 mmol, prepared according
to the Description 6 (method A) starting from the compound of
Description 11 and 2-(2-bromoethoxy)tetrahydro-2H-pyran CAS
[59146-56-4]) was dissolved in THF (5 ml) then a 5% solution of HCl
in Et.sub.2O was added. The solution was stirred for an hour and
then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc and washed with NaOH 1N, the organic phases
were dried over Na.sub.2SO.sub.4, filtered and evaporated under
vacuum to afford, after purification by flash chromatography
(CH--Cl.sub.2/MeOH/NH.sub.4OH 100/3/0.3), the title compound.
Example 2
6,7-Difluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxyli-
c acid ((S)-1-cyclohexyl-ethyl)-amide
[0230] The compound was prepared following the Description 5,
starting from the compound of Description 7 and piperazinone
CAS[5625-67-2].
Example 3
6-Fluoro-3-{4-[2-(2-hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-Imethyl}-2-ph-
enyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0231]
6-Fluoro-3-(3-oxo-4-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl-
}-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.13 g, 0.2 mmol, prepared
according to the Description 6, method A, starting from compound of
Description 9 and 2-[2-(2-chloro-ethoxy)-ethoxy]-tetrahydro-pyran
CAS[54533-84-5]) was dissolved in THF (5 ml) then a 5% solution of
HCl in Et.sub.2O was added. The solution was stirred for an hour
and then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc and washed with a 1N NaOH solution, the
organic phases were dried over Na.sub.2SO.sub.4, filtered and
evaporated under vacuum to afford, after purification by flash
chromatography (AcOEt/MeOH/NH.sub.4OH 95/5/0.5), 100 mg of the
title compound.
Example 4
(S)
3-[4-(2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-quino-
line-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0232] The compound was prepared following the Description 6,
method A, starting from the compound of Description 5 and
(S)-(-)-glycidol.
Example 5
(R)
3-[4-(2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-quino-
line-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0233] The compound was prepared following the above Description 6,
method A, starting from the compound of Description 5 and
(R)-(-)-glycidol.
Example 6
6-Fluoro-3-[4-(3-hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-quin-
oline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0234]
6-Fluoro-3-{3-oxo-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-piperazi-
n-1-ylmethyl}-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.13 g, 0.2 mmol, prepared
according to Description 6, method A, starting from the compound of
Description 9 and 2-(3-chloropropoxy)tetrahydro-2H-pyran
CAS[42330-88-1]) was dissolved in THF (5 ml) then a 5% solution of
HCl in Et.sub.2O was added. The solution was stirred for an hour
and then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc and washed with a 1N solution of, the organic
layer was dried over Na.sub.2SO.sub.4, filtered and evaporated
under vacuum to afford, after purification by flash chromatography
(AcOEt/MeOH/NH.sub.4OH 95/5/0.5), the titlecompound.
Example 7
6-Fluoro-3-[4-(3-hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-quin-
oline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0235]
6-Fluoro-3-{3-oxo-4-[3-(tetrahydro-pyran-2-yloxy)-ethyl]-piperazin-
-1-ylmethyl}-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.13 g, 0.2 mmol, prepared
according to Description 6, method A, starting from the compound of
Description 9 and 2-(2-bromoethoxy)tetrahydro-2H-pyran
CAS[59146-56-4]) was dissolved in THF (5 ml) then a 5% solution of
HCl in Et.sub.2O was added. The solution was stirred for an hour
and then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc and washed with 1N NaOH solution, the organic
layer was dried over Na.sub.2SO.sub.4, filtered and evaporated
under vacuum to afford, after purification by flash chromatography
(AcOEt/MeOH/NH.sub.4OH 95/5/0.5), the title compound.
Example 8
6
Fluoro-3-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-phenyl--
quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0236] The compound was prepared according to Description 5
starting from the compound of Description 8 and
1-hydroxyethylethoxypiperazine.
Example 9
6-Fluoro-3-[4-(3-hydroxy-propyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline--
4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0237] The compound was prepared according to Description 5
starting from the compound in Description 8 and
3-piperazin-1-yl-propan-1-ol.
Example 10
6-Fluoro-3-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-
-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0238] The compound was prepared according to Description 5
starting from the compound of Description 8 and
3-piperazin-1-yl-ethan-1-ol.
Example 11
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-thiophen-2-yl-qu-
inoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0239] The compound was prepared according to Description 5
starting from the compound of Description 10 and
1-hydroxyethylethoxypiperazine.
Example 12
3-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-c-
arboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0240] The compound was prepared according to the Description 5
starting from the compound of Description 10 and
3-piperazin-1-yl-ethan-1-ol.
Example 14
3-[4-(3-Hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-pheny3-quinoline-4-c-
arboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0241]
3-{3-oxo-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-piperazin-1-ylmet-
hyl}-2-phenyl-quinoline-4-carboxylic acid
(1-cyclohexyl-ethyl)-amide (0.4 g, 0.6 mmol, prepared according to
the Description 6, method A, starting from the compound in
Description 5 and 2-(3-chloropropoxy)tetrahydro-2H-pyran CAS
[42330-88-1]) was dissolved in THF (5 ml) then a 5% solution of HCl
in Et.sub.2O was added. The solution was stirred for an hour and
then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc washed with a 1N solution of NaOH, the
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated under vacuum to afford, after purification by flash
chromatography (AcOEt/MeOH/NH.sub.4OH 95/10/1), the
titlecompound.
Example 15
6-Fluoro-3-(2-oxo-piperazin-1-ylmethyl)-2-pheny5-quinoline-4-carboxylic
acid ((S)-1-cyclohexyl-ethyl)-amide
[0242] To a solution of
4-[4-(1-cyclohexyl-ethylcarbamoyl)-6-fluoro-2-phenyl-quinolin-3-ylmethyl]-
-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 0.8
mmol, prepared as in Description 13) in CH.sub.2Cl.sub.2 (8 ml),
TFA (0.5 ml) was added dropwise at room temperature. Stirring was
continued overnight. The solvent was evaporated under vacuum and
the residue was basified with K.sub.2CO.sub.3 saturated solution
and extracted with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
on column chromatography (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90:10:1)
to give the title compound.
Example 16
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-phenyl-qui-
noline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0243]
3-(3-oxo-4-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl}-piperaz-
in-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.13 g, 0.2 mmol, prepared
according to Description 6, method A, starting from the compound in
Description 5 and 2-[2-(2-chloro-ethoxy)-ethoxy]-tetrahydro-pyran
CAS[54533-84-5]) was dissolved in THF (5 ml) then a 5% solution of
HCl in Et.sub.2O was added. The solution was stirred for an hour
and then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc and washed with 1N NaOH solution, the organic
layer was dried over Na.sub.2SO.sub.4, filtered and evaporated
under vacuum to afford, after purification by flash chromatography
(AcOEt/MeOH/NH.sub.4OH 95/5/0.5), the title compound.
Example 17
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2-
-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0244]
3-(3-Oxo-4-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl}-piperaz-
in-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.13 g, 0.2 mmol, prepared
according to the Description 6, method A, starting from the
compound of Description 11 and
2-[2-(2-chloro-ethoxy)-ethoxy]-tetrahydro-pyran CAS[54533-84-5])
was dissolved in THF (5 ml) then a 5% solution of HCl in Et.sub.2O
was added. The solution was stirred for an hour and then the
solvents were evaporated under vacuum. The solid was re-dissolved
in EtOAc and washed with 1N NaOH solution, the organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to
afford, after purification by flash chromatography
(AcOEt/MeOH/NH.sub.4OH 95/5/0.5), the title compound.
Example 18
3-[4-(3-Hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinol-
ine-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0245]
3-(3-Oxo-4-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl}-piperaz-
in-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.13 g, 0.2 mmol, prepared
according to Description 6, method A, starting from the compound in
Description 11 and 2-(3-chloropropoxy)tetrahydro-2H-pyran CAS
[42330-88-1]) was dissolved in THF (5 ml) then a 5% solution of HCl
in Et.sub.2O was added. The solution was stirred for an hour and
then the solvents were evaporated under vacuum. The solid was
re-dissolved in EtOAc and washed with 1N NaOH solution, the organic
phases were dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness to afford, after purification by flash chromatography
(AcOEt/MeOH/NH.sub.4OH 95/5/0.5), the titlecompound.
Example 19
3-[4-((S)-2,3-Dihydroxy-propyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-
-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0246] A mixture of
2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.45 g, 1 mmol, prepared according
to Description 15), (S)-(-)-glycidol (0.2 ml, 3 mmol) and
K.sub.2CO.sub.3 (0.35 mg, 2.5 mmol) in CH.sub.3CN (10 ml) was
refluxed for 10 hours. The solvent was evaporated under vacuum and
the obtained solid was re-dissolved in EtOAc. The organic layer
washed with water, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified on column chromatography to
give the title compound.
Example 20
3-[4-((R)-2,3-Dihydroxy-propyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-
-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0247] A mixture of
2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide (0.45 g, 1 mmol, prepared according
to Description 15), (R)-(-)-glycidol (0.2 ml, 3 mmol) and
K.sub.2CO.sub.3 (0.35 mg, 2.5 mmol) in CH.sub.3CN (10 ml) was
refluxed for 10 hours. The solvent was evaporated under vacuum and
the obtained solid was re-dissolved in EtOAc. The organic phase
washed with water, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatography to
give the title compound.
Example 21
3-[4-((S)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-6-flouro-2-phe-
nyl-quinoline-4-carboxylic acid (1-cyclohexyl-ethyl)-amide
[0248] The compound was prepared following the Description 6,
method A, starting from the compound of Description 9 and
(S)-(-)-glycidol.
Example 22
3-[4-(R)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-6-fluoro-2-phen-
yl-quinoline-4-carboxylic acid (1-cyclohexyl-ethyl)-amide
[0249] The compound was prepared following the Description 6,
method A, starting from the compound of Description 9 and
(R)-(-)-glycidol.
Example 23
3-[4-((S)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-y-
l-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0250] The compound was prepared following Description 6, method A,
starting the compound in Description 11 and (S)-(-)-glycidol.
EXAMPLE 24
3-[4-((R)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-y-
l-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0251] The compound was prepared following Description 6, method A,
starting from the compound of Description 11 and
(R)-(-)-glycidol.
EXAMPLE 25
3-[4-(2-Hydroxy-ethylcarbamoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-
-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
[0252]
3-[4-(2-Bromo-ethylcarbamoyl)-piperazin-1-ylmethyl]-2-phenyl-quino-
line-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (60 mg, 1
mmol) (prepared according to Description 16 starting from the
compound in Description 15 and bromoethyl isocyanate) and sodium
acetate (40 mg, 0.5 mmol) in DMF (2 ml) were stirred for 6 hours at
80.degree. C. A saturated solution of NaCl (10 ml) was added and
the product was extracted with EtOAc. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give
the acetate derivative. The obtained crude solid was dissolved in
6N HCl (3 ml) and refluxed for 30 minutes. The solution was
basified with NaOH 1N and extracted with EtOAc. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness
to afford, after purification by flash chromatography
(AcOEt/MeOH/NH.sub.4OH 95/5/0.5), the title compound.
[0253] Examples of the present invention are provided in Table 1.
TABLE-US-00001 TABLE 1 (Examples) (I) ##STR30## Example R.sub.1
R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 Molecular Formula 1
H cyclo- Hexyl Me ##STR31## 2-thienyl H H
C.sub.29H.sub.36N.sub.4O.sub.3S 2 H cyclo- Hexyl Me ##STR32## Ph F
F C.sub.29H.sub.32F.sub.2N.sub.4O.sub.2 3 H cyclo- Hexyl Me
##STR33## Ph H F C.sub.33H.sub.41FN.sub.4O.sub.4 4 H cyclo- Hexyl
Me ##STR34## Ph H H C.sub.32H.sub.40N.sub.4O.sub.4 5 H cyclo- Hexyl
Me ##STR35## Ph H H C.sub.32H.sub.40N.sub.4O.sub.4 6 H cyclo- Hexyl
Me ##STR36## Ph H F C.sub.32H.sub.39FN.sub.4O.sub.3 7 H cyclo-
Hexyl Me ##STR37## Ph H F C.sub.31H.sub.37FN.sub.4O.sub.3 8 H
cyclo- Hexyl Me ##STR38## Ph H F C.sub.33H.sub.43FN.sub.4O.sub.3 9
H cyclo- Hexyl Me ##STR39## Ph H F C.sub.32H.sub.41FN.sub.4O.sub.2
10 H cyclo- Hexyl Me ##STR40## Ph H F
C.sub.31H.sub.39FN.sub.4O.sub.2 11 H cyclo- Hexyl Me ##STR41##
2-thienyl H H C.sub.31H.sub.42N.sub.4O.sub.3S 12 H cyclo- Hexyl Me
##STR42## 2-thienyl H H C.sub.29H.sub.38N.sub.4O.sub.2S 13 H cyclo-
Hexyl Me ##STR43## Ph H H C.sub.32H.sub.42N.sub.4O.sub.2 14 H
cyclo- Hexyl Me ##STR44## Ph H H C.sub.32H.sub.40N.sub.4O.sub.3 15
H cyclo- Hexyl Me ##STR45## Ph H F C.sub.29H.sub.33FN.sub.4O.sub.2
16 H cyclo- Hexyl Me ##STR46## Ph H H
C.sub.33H.sub.42N.sub.4O.sub.4 17 H cyclo- Hexyl Me ##STR47##
2-thienyl H H C.sub.31H.sub.40N.sub.4O.sub.4S 18 H cyclo- Hexyl Me
##STR48## 2-thienyl H H C.sub.30H.sub.38N.sub.4O.sub.3S 19 H cyclo-
Hexyl Me ##STR49## Ph H H C.sub.32H.sub.42N.sub.4O.sub.3 20 H
cyclo- Hexyl Me ##STR50## Ph H H C.sub.32H.sub.42N.sub.4O.sub.3 21
H cyclo- Hexyl Me ##STR51## Ph H F C.sub.32H.sub.39FN.sub.4O.sub.4
22 H cyclo- Hexyl Me ##STR52## Ph H F
C.sub.32H.sub.39FN.sub.4O.sub.4 23 H cyclo- Hexyl Me ##STR53##
2-thienyl H H C.sub.30H.sub.38N.sub.4O.sub.4S 24 H cyclo- Hexyl Me
##STR54## 2-thienyl H H C.sub.30H.sub.38N.sub.4O.sub.4S 25 H cyclo-
Hexyl Me ##STR55## Ph H H C.sub.32H.sub.41N.sub.5O.sub.3
[0254] TABLE-US-00002 TABLE 2 .sup.1H NMR and/or mass spectroscopy
data for Examples 1-25 Ex .sup.1H NMR (Solvent) ppm and/or MS 1
.sup.1H NMR(DMSO-d.sub.6).delta.: 8.31(d br, 1H); 8.00(d, 1H);
7.84(d, 1H); 7.82(d, 1H); 7.77(dd, 1H); 7.68(d, 1H); 7.61(dd, 1H);
7.19(dd, 1H); 4.32(t, 1H); 4.05(m, 1H); 3.87(s, 2H); 3.50(dt, 2H);
3.31(t, 2H); 3.26(t, 2H); 2.99(m, 2H); 2.63(t, 2H); 1.88-1.44(m,
7H); 1.35-1.05(m, 4H); 1.21(d, 3H). EI; TSQ 700; source 180 C; 70
V; 200 uA: 520 (M+); 378; 332; 267; 252; 223. 2 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.57(d br, 1H); 8.08(dd, 1H); 7.66(dd,
1H); 7.57-7.45(m, 6H); 3.99(m, 1H); 3.66(s, 2H); 2.86(m, 2H);
2.66(s, 2H); 2.26(m, 2H); 1.83-1.41(m, 7H); 1.29-1.00(m, 4H);
1.15(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200 uA: 506 (M+);
408; 334; 299; 282; 253 3 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.54(m,
1H); 8.12(dd, 1H); 7.73(dt, 1H); 7.55-7.42(m, 6H); 4.51(t, 1H);
3.99(m, 1H); 3.65(s, 2H); 3.50-3.30(m, 8H); 3.08(m, 2H); 2.73(s,
2H); 2.33(m, 2H); 1.83-1.39(m, 7H); 1.27-1.01(m, 4H); 1.14(d, 3H).
EI; TSQ 700; source 180 C; 70 V; 200 uA: 576 (M+); 390; 279; 264;
235; 187; 125 4 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.27(d br, 1H);
8.02(d, 1H); 7.88(d, 1H); 7.77(dd, 1H); 7.62(dd, 1H); 7.57-7.42(m,
5H); 4.31(d, 1H); 4.12(t, 1H); 4.03(m, 1H); 3.67(s, 2H); 3.63(m,
1H); 3.32(dd, 1H); 3.27(t, 2H); 3.13(m, 3H); 2.78(s, 2H); 2.40(t,
2H); 1.88-1.44(m, 6H); 1.31-1.06(m, 5H); 1.20(d,3H). EI; TSQ 700;
source 180 C; 70 V; 200 uA: 544 (M+); 372; 261; 246; 217 5 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.27(d br, 1H); 8.02(d, 1H); 7.87(d, 1H);
7.77(dd, 1H); 7.63(dd, 1H); 7.56-7.41(m, 5H); 4.31(d, 1H); 4.12(t,
1H); 4.03(m, 1H); 3.67(s, 2H); 3.63(m, 1H); 3.31(dd, 1H); 3.27(t,
2H); 3.14(m, 3H); 2.78(s, 2H); 2.40(t, 2H); 1.88-1.45(m, 6H);
1.32-1.04(m, 5H); 1.20(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200
uA: 544 (M+); 372; 261; 246; 217 6 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.31(d br, 1H); 8.10(dd, 1H); 7.67(dt,
1H); 7.54-7.43(m, 6H); 4.06(t, 1H); 4.01(m, 1H); 3.69(s, 2H);
3.36(dt, 2H); 3.23(dd, 2H); 3.00(m, 2H); 2.75(s, 2H); 2.39(dd, 2H);
1.86-1.43(m, 8H); 1.34-1.05(m, 5H); 1.19(d, 3H). EI; TSQ 700;
source 180 C; 70 V; 200 uA: 546 (M+); 390; 279; 264; 235 7 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.30(d br, 1H); 8.09(dd, 1H); 7.66(dt,
1H); 7.55-7.42(m, 6H); 4.28(t br, 1H); 4.03(m, 1H); 3.68(s, 2H);
3.45(dt, 2H); 3.25(t, 2H); 3.10(dd, 2H); 2.76(s, 2H); 2.38(dd, 2H);
1.87-1.45(m, 7H); 1.31-1.04(m, 4H); 1.19(d, 3H). EI; TSQ 700;
source 180 C; 70 V; 200 uA: 532 (M+); 406; 390; 279; 264; 235; 143
8 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.31(d br, 1H); 8.08(dd, 1H);
7.65(dt, 1H); 7.55(m, 2H); 7.51-7.40(m, 4H); 4.20(s br, 1H);
4.05(m, 1H); 3.58(s, 2H); 3.49-3.36(m, 6H); 2.37(t, 2H);
2.23-2.11(m, 8H); 1.88-1.45(m, 6H); 1.32-1.05(m, 5H); 1.21(d, 3H).
EI; TSQ 700; source 180 C; 70 V; 200 uA: 562 (M+); 501; 487; 388;
277 9 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.32(d br, 1H); 8.08(dd,
1H); 7.65(dd, 1H); 7.58-7.40(m, 6H); 4.05(m, 2H); 3.59(s, 2H);
3.40(t, 2H); 2.24(t, 2H); 2.13(m, 8H); 1.88-1.44(m, 8H);
1.34-1.05(m, 5H); 1.21(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200
uA: 532 (M+); 388; 305; 291; 279; 235; 143 10 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.34(d br, 1H); 8.08(dd, 1H); 7.65(dt,
1H); 7.58-7.40(m, 6H); 4.04(m, 1H); 3.91(s br, 1H); 3.59(s, 2H);
3.42(m, 2H); 2.29(t, 2H); 2.23-2.11(m, 8H); 1.88-1.45(m, 6H);
1.33-1.06(m, 5H); 1.21(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200
uA: 518 (M+); 500; 487; 388; 291; 279; 235; 129 11 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.29(d br, 1H); 7.98(d, 1H); 7.97(s, 1H);
7.70(d, 1H); 7.75(dd, 1H); 7.67(d, 1H); 7.60(dd, 1H); 7.18(dd, 1H);
4.28(s br, 1H); 4.05(m, 1H); 3.75(s, 2H); 3.53-3.38(m, 6H); 2.44(t,
2H); 2.38(m, 8H); 1.88-1.44(m, 6H); 1.34-1.07(m, 5H); 1.21(d, 3H).
EI; TSQ 700; source 180 C; 70 V; 200 uA: 550 (M+); 489; 475; 376;
267; 223; 173; 98 12 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.27(d br,
1H); 7.98(d, 1H); 7.97(s, 1H); 7.77(m, 2H); 7.67(d, 1H); 7.60(dd,
1H); 7.18(dd, 1H); 4.06(m, 1H); 3.95(s br, 1H); 3.75(s, 2H);
3.47(m, 2H); 2.38(m, 10H); 1.88-1.46(m, 6H); 1.32-1.06(m, 5H);
1.21(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200 uA: 506 (M+);
488; 376; 267; 223; 128 13 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.28(d
br, 1H); 8.01(d, 1H); 7.86(d, 1H); 7.75(dd, 1H); 7.62(dd, 1H);
7.57(m, 2H); 7.49-7.39(m, 3H); 4.11(s br, 1H); 4.04(m, 1H); 3.58(s,
2H); 3.40(t, 2H); 2.23(t, 2H); 2.13(m, 8H); 1.88-1.60(m, 5H);
1.57-1.45(m, 3H); .32-1.05(m, 5H); 1.20(d, 3H). EI; TSQ 700; source
180 C; 70 V; 200 uA: 514 (M+); 370; 273; 261; 143 14 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.29(d br, 1H); 8.02(d, 1H); 7.87(d, 1H);
7.77(dd, 1H); 7.63(dd, 1H); 7.55-7.41(m, 5H); 4.07(t br, 1H);
4.03(m, 1H); 3.68(s, 2H); 3.36(dt, 2H); 3.23(t, 2H); 2.99(t, 2H);
2.74(s, 2H); 2.39(t, 2H); 1.89-1.43(m, 8H); 1.32-1.05(m, 5H);
1.19(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200 uA: 528 (M+);
372; 261; 217 15 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.46(d br, 1H);
8.10(dd, 1H); 7.69(dt, 1H); 7.51-7.39(m, 6H); 4.77 and 4.69(ABq,
2H); 4.02(m, 1H); 2.90(s, 2H); 2.72(m, 2H); 2.58(m, 2H);
1.85-1.46(m, 7H); 1.33-1.02(m, 5H); 1.19(d, 3H). EI; TSQ 700;
source 180 C; 70 V; 200 uA: 488 (M+); 388; 334; 305; 279; 235 16
.sup.1H NMR(DMSO-d.sub.6).delta.: 8.14(d, 1H); 7.99(d, 1H);
7.75(dd, 1H); 7.59(dd, 1H); 7.53-7.41(m, 5H); 6.61(s br, 1H);
4.22(m, 1H); 3.77(s, 2H); 3.68(m, 2H); 3.59(m, 2H); 3.52(m, 2H);
3.44(m, 2H); 3.21(m, 2H); 3.00 and 2.94(ABq, 2H); 2.44(m, 2H);
1.87-1.40(m, 7H); 1.32-1.03(m, 5H); 1.27(d, 3H). EI; TSQ 700;
source 180 C; 70 V; 200 uA: 558 (M+); 372; 261; 245; 217; 125 17
.sup.1H NMR(DMSO-d.sub.6).delta.: 8.32(d br, 1H); 8.00(d, 1H);
7.84(d, 1H); 7.81(d, 1H); 7.77(dd, 1H); 7.67(d, 1H); 7.61(dd, 1H);
7.18(dd, 1H); 4.16(m, 1H); 4.04(m, 1H); 3.86(s, 2H); 3.49(m, 4H);
3.40(m, 4H); 3.25(m, 2H); 2.99(s, 2H); 2.16(m, 2H); 1.88-1.36(m,
6H); 1.34-1.05(m, 5H); 1.20(d, 3H). 18 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.31(d br, 1H); 8.00(d, 1H); 7.72(d, 1H);
7.80(d, 1H); 7.77(dd, 1H); 7.67(d, 1H); 7.62(dd, 1H); 7.18(dd, 1H);
4.06(m, 2H); 3.07(s, 2H); 3.39(dt, 2H); 3.29(t, 2H); 3.16(m, 2H);
2.99(s, 2H); 2.62(m, 2H); 1.86-1.36(m, 8H); 1.32-1.05(m, 5H);
1.20(d, 3H). 19 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.25(d br, 1H);
8.01(d, 1H); 7.87(d, 1H); 7.75(dd, 1H); 7.61(dd, 1H); 7.60-7.52(m,
2H); 7.51-7.40(m, 3H); 4.05(m, 2H); 3.89(m, 1H); 3.58(s, 2H);
3.54(m, 1H); 3.31(m, 2H); 2.30-2.11(m, 10H); 1.88-1.61(m, 5H);
1.52(m, 1H); 1.34-1.06(m, 5H); 1.21(d, 3H). EI; TSQ 700; source 180
C; 70 V; 200 uA: 530 (M+); 499; 469; 370; 287; 273; 261; 217 20
.sup.1H NMR(DMSO-d.sub.6).delta.: 8.25(d br, 1H); 8.01(d, 1H);
7.87(d, 1H); 7.75(dd, 1H); 7.61(dd, 1H); 7.60-7.52(m, 2H);
7.51-7.40(m, 3H); 4.05(m, 2H); 3.89(m, 1H); 3.58(s, 2H); 3.54(m,
1H); 3.31(m, 2H); 2.30-2.11(m, 10H); 1.88-1.61(m, 5H); 1.52(m, 1H).
EI; TSQ 700; source 180 C; 70 V; 200 uA: 530 (M+); 499; 469; 370;
261; 217 21 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.32(d br, 1H);
8.10(dd, 1H); 7.67(ddd, 1H); 7.56-7.42(m, 6H); 4.32(d, 1H); 4.13(t,
1H); 4.02(m, 1H); 3.68(s, 2H); 3.62(m, 1H); 3.32(dd, 1H); 3.27(t,
2H); 3.13(m, 2H); 3.12(dd, 1H); 2.78(s, 2H); 2.39(t, 2H);
1.88-1.45(m, 6H); 1.32-1.03(m, 5H); 1.18(d, 3H). 22 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.30(d br, 1H); 8.10(dd, 1H); 7.67(dt,
1H); 7.56-7.42(m, 6H); 4.30(d br, 1H); 4.11(t br, 1H); 4.03(m, 1H);
3.68(s, 2H); 3.63(m, 1H); 3.35-3.25(m, 3H); 3.17-3.10(m, 3H);
2.78(s, 2H); 2.39(t, 2H); 1.87-1.47(m, 6H); 1.30-1.05(m, 5H);
1.19(d, 3H). EI; TSQ 700; source 180 C; 70 V; 200 uA: 562 (M+);
390; 279; 264; 235 23 .sup.1H NMR(DMSO-d.sub.6).delta.: 8.33(d br,
1H); 8.00(d, 1H); 7.84(d, 1H); 7.81(d, 1H); 7.77(dd, 1H); 7.67(d,
1H); 7.61(dd, 1H); 7.19(dd, 1H); 4.37(d br, 1H); 4.16(t br, 1H);
4.05(m, 1H); 3.87(s, 2H); 3.67(m, 1H); 3.38(dd, 1H); 3.30(m, 4H);
3.19(dd, 1H); 3.02(s, 2H); 2.63(t, 2H); 1.86-1.45(m, 6H);
1.31-1.05(m, 5H); 1.21(d, 3H). 24 .sup.1H NMR(DMSO-d.sub.6).delta.:
8.32(d br, 1H); 8.00(d, 1H); 7.84(d, 1H); 7.81(d, 1H); 7.77(dd,
1H); 7.67(d, 1H); 7.61(dd, 1H); 7.19(dd, 1H); 4.35(d br, 1H);
4.14(t br, 1H); 4.05(m, 1H); 3.87(s, 2H); 3.67(m, 1H); 3.38(dd,
1H); 3.30(m, 4H); 3.19(dd, 1H); 3.02(s, 2H); 2.63(t, 2H);
1.86-1.45(m, 6H); 1.31-1.05(m, 5H); 1.21(d, 3H). 25 .sup.1H
NMR(DMSO-d.sub.6).delta.: 8.24(d br, 1H); 8.02(d, 1H); 7.86(d, 1H);
7.76(dd, 1H); 7.62(dd. 1H); 7.56(m, 2H); 7.51-7.40(m, 3H); 6.04(t
br, 1H); 4.23(t br, 1H); 4.04(m, 1H); 3.60(s, 2H); 3.38(dt, 2H);
3.07(dt, 2H); 3.01(m, 4H); 2.08(m, 4H); 1.88-1.44(m, 6H);
1.31-1.04(m, 5H); 1.20(d, 3H).
[0255] TABLE-US-00003 TABLE 3 Melting points (Mp/.degree. C.)
and/or Refractory indices (|.alpha.|.sub.D.sup.20) of Examples 1-25
Example Number Mp (.degree. C.) |.alpha.|.sub.D.sup.20 1 212-215
-8.61 (c = 0.1%, MeOH) 2 185-190 +14.2 (c = 0.5%, MeOH) 3 110-112
+5.43 (c = 0.1%, MeOH) 4 125-127 -5.01 (c = 0.1%, MeOH) 5 133-135
+7.49 (c = 0.1%, MeOH) 6 110-130 +10.08 (c = 0.1%, MeOH) 7 120-122
+12.95 (c = 0.5%, MeOH) 8 142-144 +19.37 (c = 0.1%, MeOH) 9 182-184
+18.33 (c = 0.1%, MeOH 10 114-116 +17.52 (c = 0.1%, MeOH 11 182-188
-36.65 (c = 0.1%, MeOH 12 110 +23.09 (c = 0.1%, MeOH) 13 168-170
-16.9 (c = 0.15%, MeOH) 14 120-122 -12.68 (c = 0.15%, MeOH) 15
240-242 -17.15 (c = 0.125%, MeOH) 16 125-128 +12.56 (c = 0.1%,
MeOH) 17 102-104 +9.84 (c = 0.1%, MeOH) 18 117-119 +9.82 (c = 0.1%,
MeOH) 19 124-126 +24.35 (c = 0.11%, MeOH) 20 126-128 +12.46 (c =
0.12%, MeOH) 21 190-192 +14.2 (c = 0.1%, MeOH) 22 143-145 +8.42 (c
= 0.1%, MeOH) 23 115-117 +17.9 (c = 0.5%, MeOH) 24 118-121 -20.5 (c
= 0.5%, MeOH) 25 155-157 +13.5 (c = 0.1%, MeOH) -- -- --
[0256] TABLE-US-00004 TABLE 4 Chemical names of parent compounds of
Examples 1-25 (names generated by Beilstein's Autonom) Ex Chemical
name 1 3-[4-(2-Hydroxy-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-
thiophen-2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 2
6,7-Difluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-
4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 3
6-Fluoro-3-{4-[2-(2-hydroxy-ethoxy)-ethyl]-3-oxo-
piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide 4 (S)
3-[4-(2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
5 (R) 3-[4-(2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
6 6-Fluoro-3-[4-(3-hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
7 6-Fluoro-3-[4-(2-hydroxy-ethyl)-3-oxo-piperazin-1-ylmethyl]-
2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
8 6-Fluoro-3-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-
ylmethyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 9
6-Fluoro-3-[4-(3-hydroxy-propyl)-piperazin-1-ylmethyl]-2-
phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
10 6-Fluoro-3-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-2-
phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
11 3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-
2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 12
3-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-thiophen-
2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 13
3-[4-(3-Hydroxy-propyl)-piperazin-1-ylmethyl]-2-phenyl-
quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 14
3-[4-(3-Hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-phenyl-
quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 15
6-Fluoro-3-(2-oxo-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-
carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 16
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-
ylmethyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-
cyclohexyl-ethyl)-amide 17
3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-3-oxo-piperazin-1-
ylmethyl}-2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-1-
cyclohexyl-ethyl)-amide 18
3-[4-(3-Hydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-2-
thiophen-2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-
amide 19 3-[4-((S)-2,3-Dihydroxy-propyl)-piperazin-1-ylmethyl]-2-
phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
20 3-[4-((R)-2,3-Dihydroxy-propyl)-piperazin-1-ylmethyl]-2-
phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide
21 3-[4-((S)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
6-fluoro-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 22
3-[4-((R)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
6-fluoro-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 23
3-[4-((S)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 24
3-[4-((R)-2,3-Dihydroxy-propyl)-3-oxo-piperazin-1-ylmethyl]-
2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-
ethyl)-amide 25
3-[4-(2-Hydroxy-ethylcarbamoyl)-piperazin-1-ylmethyl]-2-
phenyl-quinoline-4-carboxylic acid
((S)-1-cyclohexyl-ethyl)-amide
* * * * *